Maintenance of two measured ABG parameters, pO₂(a) and pCO₂(a) within normal limits implies effective pulmonary gas exchange, which is dependent on:

• Adequate alveolar ventilation. This is the movement of air in and out of alveoli due to the mechanical process of breathing that depends on the chest musculature and elastic recoil of the lungs.
• Normal numbers of functioning alveoli.
• Normal thickness of alveolar-capillary membrane.
• Sufficient blood flow through pulmonary capillaries (i.e. adequate alveolar perfusion).
• No significant ventilation/perfusion mismatch (mismatch occurs, for example, if alveoli are well perfused with blood but inadequately ventilated with air).
• Intact brain stem (explained below).

Ventilation is continuously regulated, principally by respiratory centers located in the brain stem. These respond to the amount of CO₂ in arterial blood (i.e. the pCO₂(a)), detected by closely associated chemoreceptor cells. By their neural connection to the chest musculature involved in breathing, these respiratory centers increase the rate and depth of breathing, and thereby increase alveolar ventilation, if pCO₂ is rising and reduce alveolar ventilation if pCO₂(a) is falling. 

By this means sufficient CO₂ is eliminated in expired air to maintain pCO₂(a) within narrow normal limits.

Inappropriately reduced ventilation (hypoventilation) leads to inadequate pulmonary gas exchange, evident on blood gas analysis as increased pCO₂ and decreased pO₂(a).

Hyperventilation (overbreathing) is always associated with decreased pCO₂(a) but not necessarily, as might be supposed, increased pO₂(a).

BLOOD TRANSPORT OF OXYGEN - TWO ABG PARAMETERS (pO₂(a) AND sO₂)

Oxygen is poorly soluble in blood and the small amount of oxygen that can be transported simply dissolved in blood (~3.0 mL of oxygen per liter of blood) is quite inadequate to satisfy tissue demand for oxygen.

The oxygen-carrying protein, hemoglobin, contained in the cells of blood (specifically the red cells or erythrocytes) provides an additional, far more effective, means of transporting oxygen, and increases the oxygen-carrying capacity of blood from ~3.0 to ~200 mL oxygen per liter. 

In fact only 1-2 % of the oxygen transported in blood is dissolved in the aqueous phase of blood; this is the portion that is measured by the pO₂(a).

The remaining 98-99 % is transported in erythrocytes bound to hemoglobin.

Each erythrocyte contains 250-300 million hemoglobin molecules and each hemoglobin molecule can bind a maximum of four oxygen molecules.

The product of the reversible binding of oxygen by hemoglobin is called oxyhemoglobin; the term deoxyhemoglobin is used to describe hemoglobin that has no oxygen bound to it.

The oxygen delivery function of hemoglobin, i.e. its ability to ”pick up” oxygen in the lungs and ”release” it in the microvasculature of tissue cells, is made possible by a reversible conformational change in the quaternary structure (shape) of the hemoglobin molecule that alters its affinity for oxygen. In the deoxy state hemoglobin has low affinity for oxygen and in the oxy state it has high affinity for oxygen. 

A number of environmental factors in blood determine the hemoglobin state (deoxy or oxy) and thereby the relative affinity for oxygen.

The most significant of these is the pO₂. Hemoglobin present in blood with relatively high pO₂ has much greater affinity for oxygen than hemoglobin present in blood with relatively low pO₂. The oxygen dissociation curve (ODC) describes this relationship graphically (Fig. 1). 

The percentage of total hemoglobin saturated with oxygen (i.e. oxygen saturation, sO₂) is the measure of hemoglobin affinity in this graph.

It is clear from the graph that at the high pO₂ that prevails in the blood exposed to alveolar air in the lung (~13 kPa), hemoglobin is almost 100 % saturated with oxygen; nearly all of the available oxygen-binding sites on the totality of hemoglobin molecules are occupied with oxygen. 

By contrast in the milieu of the tissues where pO₂ is much lower, hemoglobin affinity for oxygen is also much lower and oxygen is released from hemoglobin to the tissues. 

The hemoglobin in venous blood leaving the tissues consequently has less oxygen bound to it and this is reflected in the much lower sO₂ of venous blood (sO₂(v) ~70 %) compared to that of arterial blood (sO₂(a) >95 %).

 

Fig.1: Oxygen dissociation curve. Relationship between the amount of oxygen dissolved in blood (PO₂) and the amount of oxygen carried by hemoglobin (SO₂).

Although pO₂(a) only reflects a tiny proportion (1-2 %) of the oxygen in arterial blood, it is highly significant because it determines the amount of oxygen bound to hemoglobin (the sO₂(a)) and thereby the total amount of oxygen that is contained in arterial blood for delivery to tissues. If pO₂(a) is reduced, then less oxygen can be carried by hemoglobin (i.e. sO₂(a) is reduced) and less oxygen is available to tissues. 

Examination of the oxygen dissociation curve (Fig. 1) reveals that a significant decrease in pO₂(a) from 16 kPa to 10 kPa has only slight effect on sO₂(a) and therefore the oxygen-carrying capacity of blood, but there is a sharp fall in sO₂(a) as pO₂(a) falls below 10 kPa. The delivery of oxygen to tissues becomes increasingly compromised as pO₂(a) falls below this level.

For optimum oxygenation of tissues:

• Blood must contain an adequate amount of hemoglobin.
• That hemoglobin must be >95 % saturated with oxygen in arterial blood (sO₂(a) >95 %).
• To achieve sO₂ (a) >95 %, pO₂ (a) must be >10.6 kPa (80 mmHg).
• Maintenance of pO₂(a) above 10.6 kPa depends on the factors required for effective pulmonary gas exchange (see above).

ACID-BASE BALANCE: THE MAINTENANCE OF NORMAL BLOOD pH
In this section we turn the attention away from the ABG parameters that reflect blood oxygenation (pO₂(a), sO₂(a)) to those that reflect acid-base balance. They are: pH, pCO₂(a), bicarbonate concentration (HCO₃^– ) and base excess. pCO₂(a) has already been introduced in the discussion of pulmonary gas exchange, and its inclusion here reflects the central role that the lungs play in the maintenance of blood pH.

All biochemical reactions are sensitive to change in pH, so that optimum survival and function of cells require that blood pH is maintained within the narrow range of 7.35-7.45, despite normal cell metabolism being associated with the production of metabolic acids.

Even mild excursion outside the normal range has multiple deleterious effects, and a pH of less than 6.8 or greater than 7.8 is incompatible with life. 

The maintenance of normal blood pH is a complex synergy of action involving the chemical buffers present in blood (principally bicarbonate), red blood cells and the function of three organs: the kidneys, lungs and brain stem.

The following discussion assumes an outline understanding of some basic concepts: pH, acids, bases and buffers (see BOXES 2-4 for a reminder).

To understand the maintenance of blood pH and the other ABG parameters used to assess acid-base balance, it is useful to consider the way carbon dioxide (CO₂) is transported in blood from tissue cells to lungs. In the microvasculature of tissues CO₂ diffuses from cells –where it is produced – to blood due to the prevailing pCO₂ gradient (pCO₂ in tissue cells higher than that in blood). 

A small amount (~5 %) remains simply dissolved in blood plasma and the cytoplasm of erythrocytes, and a similar amount is carried in erythrocytes bound to hemoglobin that has yielded up its oxygen to tissues, but most (90 %) is hydrated to carbonic acid in erythrocytes by the action of the enzyme carbonic anhydrase. Nearly all (~96 %) of this carbonic acid rapidly dissociates, yielding bicarbonate and hydrogen ions, thus (reaction should be read from left to right):    
                           _{carbonicanhydrase} 
     CO ₂x+ H₂O <-----------------> H₂CO₃ <-----------------> HCO₃^- + H⁺

The potentially dangerous fall in red-cell pH induced by the influx of hydrogen ions is ameliorated by them combining with reduced hemoglobin (hemoglobin, now stripped of its oxygen is acting as a buffer here). Around 65% of the bicarbonate passes from erythrocytes and is transported in blood plasma; the rest remains in the cytoplasm of erythrocytes.

When venous blood arrives in the capillary networks that surround the alveoli in the lungs, the small amount of CO₂ dissolved in blood passes across the alveolar membrane due to the prevailing pCO₂ gradient. This loss of CO₂ from blood reverses the direction of the above equation (should now be read from right to left) reflecting a reversal of the sequence of events that occurred in the microvasculature of the tissues. So, in blood perfusing the alveoli, hemoglobin releases hydrogen ions as it combines with inspired oxygen. 

These hydrogen ions are buffered by (combine with) bicarbonate to form carbonic acid, which dissociates to carbon dioxide (CO₂) and water. The CO₂ diffuses from blood to alveoli. The process is continuously regulated so that the amount of CO₂ being removed from blood at the lungs equals the amount of CO₂ being added to the blood in the tissues.

To summarize, there are four ways in which CO₂ is transported in blood:

• 5 % is transported simply dissolved in plasma and erythrocyte cytoplasm. pCO₂(a) is a measure of this small portion of total CO₂.
• 90 % is transported as bicarbonate (the principal blood buffer) (the concentration of bicarbonate (mmol/L) is calculated during ABG).
• 5 % is transported loosely bound to hemoglobin in red cells.
• <0.1 % is transported as carbonic acid.

THE SYNERGISTIC ROLE OF LUNGS AND KIDNEY IN MAINTAINING NORMAL BLOOD pH
The following relationship between three ABG parameters pH, pCO₂(a) and bicarbonate (HCO₃^–) is derived from the Henderson-Hasselbalch equation for the bicarbonate buffer system in blood (see BOX 4):

This simple relationship, which is central to an understanding of all essential aspects of acid-base balance and interpretation of patient ABG results, states that pH of arterial blood is a function of both pCO₂(a) and bicarbonate concentration. pH falls if either pCO₂(a) is increased or bicarbonate is reduced, and pH rises if either pCO₂(a) is reduced or bicarbonate is increased. The relationship also reveals that pH remains unchanged if both bicarbonate and pCO₂(a) are increased or decreased by the same relative amount.

The inverse relationship between pH and pCO₂(a) reflects the acidic potential of carbon dioxide (remember that when dissolved in blood, carbon dioxide is hydrated to carbonic acid, which dissociates yielding hydrogen ions, see equation above). As already discussed, the process of pulmonary gas exchange in the lungs ensures that pCO₂(a) remains constant and in so doing ensures a vital contribution to the maintenance of normal pH. Clearly if through disease or injury the lungs were unable to eliminate carbon dioxide efficiently, pCO₂(a) would rise and pH would fall.

Bicarbonate concentration, the nominator in the above equation is dependent on normal kidney function.

As the principal buffer in blood, bicarbonate prevents the rapid change in pH that would otherwise occur, when in the normal course of cell metabolism, metabolic acids are released to blood. Bicarbonate ”mops up” the hydrogen ions from these metabolic acids, thereby preventing a fall in pH. 

As bicarbonate is consumed in this process, it is of itself a very short-term solution to the problem of maintaining the pH of blood to which acids are being added.

For continuing effectiveness, bicarbonate must be continuously re-generated and the hydrogen ions they are buffering must be removed from the body.

These two tasks are the work of the kidneys. By adjusting the excretion of hydrogen ions and bicarbonate in urine, and thereby the reabsorption of bicarbonate to blood, the kidneys maintain blood concentration of bicarbonate within normal limits. This in turn is essential to the maintenance of normal blood pH.

Maintenance of normal pH depends on:

• Preserving normal pCO₂(a) (this in turn depends on adequate pulmonary gas exchange and therefore normally functioning lungs and brain stem).
• Preserving normal bicarbonate concentration (this in turn depends on normally functioning kidneys).

The respiratory and renal systems outlined above operate together in maintaining blood pH. Since preservation of blood pH within the normal range is paramount, the normal response to a fall in bicarbonate is a compensatory adjustment downwards of pCO₂(a).

Remember, it is the ratio of bicarbonate: pCO₂(a) that must be preserved, if pH is to be maintained within the normal range.