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Regulation of acid-base balance

The pH of all body’s extracellular fluids must be regulated in order to stay between a value
of 7.35 and one of 7.45, the normal range.
The balance is achieved through mainly three defense mechanism: the chemical buffering,
the respiratory compensation (pCO2 alteration), and the renal compensation (HCO− 3
alteration). Conditions of disequilibrium can occur:
 Acidosis: increased acids/ decreased bases concentration in the body
 Alkalosis: increased bases/decreased acids concentration in the body
Acid-base disorders are classified based on whether there is a primary change in pCO 2 or
in HCO− −
3 , with respiratory changes mainly involving pCO2, and metabolic changes HCO3 or
fixed acids.

Buffer systems are mechanisms aimed at maintaining pH levels in the normal range:
inside the cell the main buffers are phosphate and proteins, in the urine the two major
buffers are phosphate and ammonia. One of the most important buffer systems in our
body is the bicarbonate buffer.


It’s an homeostatic mechanism which aims at maintaining pH in blood (and other tissues),
by balancing H2CO3 (carbonic acid), CO2 (carbon dioxide) and HCO− 3 (bicarbonate ion).
The optimum ratio of bicarbonate over carbonic acid is 20, ratio corresponding to pH=7.4 .
In order to maintain this pH, our body will adjust bicarbonate (through kidney), carbonic
acid and pCO2 (through lungs) to keep the ratio around 20.

A hypothetical situation of high CO2 and high HCO3− could both be a case of
 Respiratory acidosis (partially or totally compensated by an increase in HCO3− )
 Metabolic alkalosis (partially or totally compensated by an increase in pCO2)
If the pH is acidic we will probably tend to acidosis, if it’s alkaline most probably to
alkalosis. This last assumption could work If we assume that there is only one disorder
going on, but most of the times acid-base disorders are combined.
So to properly identify the problem, one has to assess whether the acid-base changes in
the patient are just occurring as a compensation for a primary disorder or are a
combination of multiple disorders.
So we have to distinguish between:
 Simple acid-base disorder: only one primary mechanism
 Mixed acid-base disorders: coexistence of two or more primary disorders

Furthermore, we also distinguish
 Acidosis/Alkalosis which are the processes, no matter if compensated or not. Two
antagonizing processes could coexist resulting in a normal pH
 Acidemia/Alkalemia which are just a measure of pH unbalances, the former being
a pH lower than 7.35, the latter being a pH higher than 7.45.

A way to understand whether we have a simple acid base disorder or mixed acid base
disorders is by looking at a normogram (image below): if the values of HCO3− and pH of
the patient are found inside of the shaded areas, it’s most probably a simple disorder with
normal compensation, if the values are found outside instead, we may tend to think there
is the coexistence of multiple disorders.

The four main acid-base disorders we are about to discuss are:
 Metabolic Acidosis
 Metabolic Alkalosis
 Respiratory Acidosis
 Respiratory Alkalosis


Primary disorder: gain of fixed, nonvolatile acids and/or loss of HCO− 3 in the blood (since
the acidosis is metabolic, the acids, being nonvolatile, can’t be eliminated through lungs).
Compensation: hyperventilation

So the most common pattern would be: HCO− 3 decrease, leading to a pCO2 decrease due
to hyperventilation as a compensation mechanism.
Metabolic acidosis could occur due to:
 Gain of extra acids like: ketone bodies, lactic acid, uric acid, toxins; anything
acidic which is being added to the system and that will titrate down HCO− 3.
 Loss of 𝐇𝐂𝐎𝟑 due to: diarrhea, kidney problems (particularly tubular acidosis)

So we either have metabolic acidosis due to acidic gain or due to alkaline loss.
In order to properly distinguish between the two, the anion gap is of use:
Anion Gap: [Na+] – ([Cl-] + [𝐇𝐂𝐎− 𝟑 ]) = 8 to 16 mEq/L (as normal reference value).

The anion gap is the difference between primary measured cations (Na + and K+) and the
primary measured anions (Cl- and HCO3− .) in serum.
 A gain of acids will result in an increase in the Anion Gap, due to anions which
are added
 A loss of 𝐇𝐂𝐎− −
𝟑 will instead give a normal Anion Gap, because HCO3 is
substituted by Cl-, to reestablish electroneutrality)

Another useful parameter is the Delta Ratio, given by: increase in anion gap/decrease in
bicarbonate. Normally, in the presence of a fixed acid, the AG will increase more than the
decrease in HCO−3 ; now, a ratio of:
 1 to 2 is a synonym of classical AG acidosis
 0,4 to 0,8 is most probably indicative of a mixed loss of HCO− 3 together with gain of
acids, which is typical of uremia.
 > 2 there is more HCO− 3 than we would reasonably expect, indicating possibly a
coexistence of disorders (like metabolic alkalosis).

So, summarizing, metabolic acidosis can be classified based on the anion gap: wither as a
gain of endogenous/exogenous acids (increased anion gap) or hyperchloremic acidosis
(normal anion gap).


Primary disorder: increase in plasma [HCO− 3]
Compensation: hypoventilation, aimed at increasing pCO2
Metabolic Alkalosis could occur due to:
 Loss of acids (emesis or extensive use of diuretics)
 Gain of alkali (excessive ingestion of bicarbonate or due to some other rare
conditions like the milk-alkali syndrome).
Besides the initiating event, we need a maintenance event, preventing the body from
getting rid of the excess bicarbonate. The main possible maintenance events are:
 Cl- depletion: during vomiting, chloride and protons (H+) are lost; bicarbonate is
retained due to this HCl loss. The body thus needs bicarbonate in order to maintain
electroneutrality, due to chloride absence. A similar situation could arise due to an
extensive use of diuretics.
 K+ depletion is caused by: hypokalemia, hyperaldosteronism, rare genetic
syndromes (such as Liddle’s syndrome or Bartter’s syndrome).

In order to properly treat the patient, one must assess whether there is a problem in
chloride or potassium in metabolic alkalosis, so Cl- in urines should be checked.
Chloride depletion comes with low chloride in urines (<10 mmol), whereas
hyperaldosteronism or K+ depletion usually come with higher Cl- in urines (>20 mmol).


Primary disorder: arterial CO2 increase, mostly due to respiratory dysfunction
Compensation: increase in [HCO− −
3 ] because the system tends to keep the [HCO3 ]/pCO2

ratio close to 20 (pH = 7.4). [HCO3 ] can increase as high as 40 mEq/L, almost twice as
normal value (24 mEq/L).
The bicarbonate thus increases due to compensation:
 CHEMICAL COMPENSATION, recalling the formula of CO2 dissociation:

If pCO2 increases, the equilibrium will be shifted to the right and more
bicarbonate will be thus produced. This is the first line of compensation, which
happens at the beginning and it’s just chemical.
 BIOLOGICAL COMPENSATION (which happens in the following hours and days),
kidneys start to produce more ammonia and to retain more bicarbonate. Now
compensation will be much more effective compared with the initial chemical
So in the first hour [HCO3− ] is expected to increase but not dramatically, so if a substantial
increase in [HCO3− ] is found, it’s more unlikely to think of respiratory acidosis.

But what causes pCO2 retention?
 Hypoventilation, due to various causes (neurologic level of control, neuromuscular
control, lung and chest control, airways obstruction). Problems at any of these
levels will necessarily compromise ventilation, leading to a CO2 retention and
subsequently to a defect in blood oxygenation. About 90% of the cases of
respiratory acidosis come from these situations.
 Excess of CO2 production, which is not particularly frequent, but it may happen in
malignant hyperthermia, a disease of muscles, and also in the case of sepsis. Any
kind of hypermetabolic condition can potentially increase CO2 to such a level that
lungs are not able to eliminate all of it, but they are not extremely frequent because
usually the lungs are efficient in properly eliminating CO2, unless the patient has
very serious ventilation problems.


Primary disorder: arterial pCO2 decrease
Compensation: initial compensation accounts for a decrease in plasma bicarbonate
concentration up to 12-15 mmol/L.

If a patient has a particularly low level of bicarbonate concentration, like 9-10 mmol/L,
whatever the pH is, we can exclude it is due to this kind of compensation mechanism,
because the values would not be this low. This would suggest the coexistence of other
disorders, such as metabolic acidosis, for example.

Causes of respiratory alkalosis are any possible cause of hyperventilation, such as:
 Hypoxia, hypoxemia, severe anemia
 Activation of the central respiratory center (due to anxiety, fever, drugs, trauma)
 Physical exercise
 Lung disorders (edema, pneumonia, embolism)
 Liver disease
Now, since it’s difficult to determine whether it’s a single acid-base disorder with normal
compensatory mechanisms or possibly multiple primary acid-base disorders coexisting,
bedside rules are adopted which allow to understand. These are based on the rationale
of how much bicarbonate change we would expect in respiratory acidosis/alkalosis and
how much CO2 change we would expect in metabolic acidosis/alkalosis.
For respiratory alkalosis/acidosis, both acute and chronic, we have:

 Acute respiratory acidosis (<2 days duration), 1 for 10 rule: the bicarbonate
concentration should rise by 1 mmol/L for every 10 mmHg rise in pCO 2 above the
midpoint of the normal range (40 mmHg). That’s a relatively low value, that’s why
it’s acute.
 Chronic respiratory acidosis (>2 days duration), 4 for 10 rule: the bicarbonate
concentration should rise by 4 mmol/L for every 10 mmHg rise in pCO 2 above the
midpoint of the normal range (40mmHg).
 Acute respiratory alkalosis (<2 days duration), 2 for 10 rule: the bicarbonate
concentration should fall by 2 mmol/L for every 10 mmHg fall in pCO2 below the
midpoint of the normal range (40mmHg).
 Chronic respiratory alkalosis (>2 days duration), 5 for 10 rule: the bicarbonate
concentration should fall by 5 mmol/L for every 10 mmHg fall in pCO2 below the
midpoint of the normal range (40mmHg).

Instead, for metabolic disorders, there are no differences between acute and chronic:

 Metabolic acidosis: predicted CO2 : pCO2 (mmHg) = (1.5[HCO−3 ] + 8) ± 2
 Metabolic alkalosis: predicted CO2 : pCO2 (mmHg) = (0.7[HCO−3 ] + 20) ± 5

If actual values differ significantly from expected values, it’s most likely there are multiple
processes occurring at the same time.

Silvio Baccaro