Transport of carbon dioxide in the blood

This chapter is most relevant to Section F8(iii) from the 2023 CICM Primary Syllabus, which expects the exam candidates to be able to "describe the carbon dioxide carriage in blood". The college examiners love this topic, and it has come up several times in the First Part papers:

Of the college examiner comments for these questions, none are more helpful than the comments for Question 13 from the first paper of 2015, which offer a clear outline of what was expected.

In summary:

CO2 is transported by three major mechanisms:

  • As bicarbonate (HCO3), 70-90% of total blood CO2 content
    • Combined with water, COforms carbonic acid, which in turn forms bicarbonate:
      CO2 + H2O ⇌ H2CO⇌ HCO3- + H+
    • This mainly happens in RBCS
    • The rise in intracellular  HCO3- leads to the exchange of bicarbonate and chloride, the chloride shift. Chloride is taken up by RBCSs, and bicarbonate is liberated.
    • Thus chloride concentration is lower in systemic venous blood than in systemic arterial blood
  • As carbamates, the conjugate bases of carbamino acid (about 10-20%)
    • Dissociated conjugate bases of carbamino acids, which form in the spontaneous reaction of R-NH2 and CO2.
    • Intracellular (RBC) carbamino stores are the greatest: haemoglobin, particularly deoxygenated haemoglobin, has a high affinity for CO2, whereas most other proteins do not
  • As dissolved CO2 gas, about 10%
    • Henry's law states that the amount of dissolved gas in a liquid is proportional to its partial pressure above the liquid
    • Thus, for every 1 mmHg of pCO2 the blood concentration increases by about 0.03 mmol/L
    • Thus, CO2 is 10-20 times more soluble than oxygen 
  • Carbonic acid: 
    • A miniscule proportion of total carbon dioxide exists in this form, i.e. it is not a major contributr to CO2 transport

There is a difference between arterial and venous CO2 content:

  • Mixed venous blood has a total CO2 content of  about 22.5 mmol/L
    (or 520 mL/L)
  • Arterial blood has a total CO2 content of about 20.5 mmol/L 
    (or 480ml/L)
  • Much of this difference is due to the increase in bicarbonate concentration (85%)
  • Some of this difference is also due to the Haldane effect:
    • Deoxyhaemoglobin has about 3.5 times the affinity for CO2 when compared to oxyhaemoglobin
    • This increases the CO2 binding capacity of venous blood
    • Deoxyhaemoglobin is also a better buffer than oxyhaemoglobin, which increases the capacity of RBCs to carry HCO3-

The most relevant references for this topic are Chapter 4.5 from "Acid-Base Physiology" by Brandis, as well as this excellent free review article by Geers & Gros (2000). If one is able to do so, one should make every effort to gain access to Klocke (2011), which is unfortunately paywalled, but which is comprehensive beyond reproach better referenced than Nunn's.

Proportions of different CO2 transport mechanisms

There appears to be some disagreement among publications with regards to how much CO2 is transported, and where. For instance, various basic-level review articles (such as Arthurs & Sudhakar, 2005) state authoritatively that "approximately 75% of carbon dioxide is transport (sic) in the red blood cell and 25% in the plasma". In contrast, Geers & Gros (2000,  Table 1) give quite a different set of numbers, almost totally the reverse. Given that the latter article quotes good references and the former does not, the author had gullibly attributed to it a greater credibility and crudely reassembled their borrowed data as a series of coloured cylinders:

Diagrams of CO2 transport mechanisms in whole blood

Or, to present it in a slightly different way:

Different modes of CO2 transport in the blood

Or, if one prefers actual data:

Carbon Dioxide Content of the Blood
  Arterial blood (mmol/L)

Mixed venous blood (mmol)L)

Plasma: dissolved CO2 0.68 0.78
Plasma: bicarbonate 13.52 14.51
Plasma: carbamate 0.3 0.3
RBC dissolved CO2 0.4 0.46
RBC bicarbonate 5.01 5.46
RBC carbamate 0.75 0.84
Total CO2 content of acellular plasma 14.5 15.59
Total CO2 content of RBCs 6.16 6.76

This is a handy segue into the discussion of the difference between arterial and venous caron dioxide content.

Difference between arterial and venous CO2 content

Though this is not explicitly stated in the question stem ("describe the carriage of carbon dioxide (CO2) in the blood") the college examiners expected exam candidates to produce "a table of the contribution of each form of carriage to arterial and venous content and the AV difference" in their answer to Question 5 from the second paper of 2018.

The normal difference between PaCO2 and PvCO2 is usually said to be about 2-6 mmHg (Groeneveld, 1998), but this is a difference of tension rather than of content. Content should really be measured in units of content, for one. Some authors report ml/L, and others mmol/L. The data from Geers & Gros (2000) suggests that this difference is not massive.

Difference between Arterial and Venous
Carbon Dioxide Content

Difference in mmol/L
(and % contribution to the a-v difference)

Dissolved 1.08 1.24 0.16   (9.5%)
Bicarbonate 18.53 19.97 1.44   (85.2%)
Carbamates 1.05 1.14 0.09   (5.3%)
Total (mmol/L) 20.66 22.35 1.69  (100%)

The attentive reader will have noted that this table is in disagreement with Nunn, that is to say in opposition to the official CICM textbook. Nunn's Applied Respiratory Physiology, the 8th ed (2017), contains this table:

Table 9.2 from Nunns (8th ed)

Assuming the units of measurement for everything are in mmol/L, this table would seem to suggest that the carbamates contribute 0.6 mmol/L of the total 1.8 mmol/l difference between arterial and venous CO2 content, not 0.09 mmol/L. Nunns has not references, but we know that the values from  Geers & Gros come from measurements collected by Gros et al in 1976.

So which value is correct, and more importantly, what should the trainees mention in their exam answers?  This is frustrating, because depending on which resource one decides to quote, one may be wrong by about 10%.  Observe:

Carbamino Compound Contribution
to Carbon Dioxide Carriage, 

Depending on Which Textbook You Read

  Arterial Venous

Difference (and % ) of total a-v difference in CO2 content

Nunn's 8th ed 1.10 mmol./L 1.70 mmol/L 0.60 mmol/L
Ganong, 23rd ed (p.613) 2.6 ml/dl
(1.02 mmol/L)
3.2 ml/dl
(1.26 mmol/L)
0.8 ml/dl (0.24 mmol/L, 25%)
Guyton & Hall, 13th ed, p.535 ? 1.5 ml/dl
(0.59 mmol/L)
"about 30 percent"
Boron & Boulpaep, 3rd ed (p.656) 1.2 mmol/L 1.6 mmol/L 0.4 mmol/L, 21% 
Kam (3rd ed, p96) ? ? "About 1/3rd"
Stoelting (2015) ? ? ?
Brandis ? ? 30%
Geers & Gros (2000) 1.05 mmol/L 1.14 mmol/L 0.09  mmol/L  (5.3%)
Klocke (2011) 1.5 mmol/L 1.74 mmol/L 0.24 mmol/L (12.6%)

Basically all of these authors for some reason report CO2 in ml/dl,  which is a measure of volume rather than content. This would be fine if they respected the Universal Gas Law and concurrently reported the temperature and pressure, as for example, one could pack 100 moles of CO2 into 2.6 mL of space provided one subjected it to 960,000 atmospheres of pressure (roughly what one might expect about 10,000 km below the surface of the cloud layers of Jupiter). To double-check the values above, ordinarily the readers would be invited to use this excellent free online Ideal Gas Law Calculator, but this would of course be a waste of their time, as the consensus of textbooks seems to be in favour of the "about 1/3rd" value, and this is what examiners will probably be expecting, as question marking rubrics are written on the basis of the official textbooks. 

In summary: if the physiology Gestapo come asking, you tell them carbamino compounds contribute about one third to the total arteriovenous difference in CO2 carriage.

But wait. Surely this value must come from somewhere? Readers unsatisfied with this state of affairs will probably also want to know why eminent professors have decided to include it in the book chapters their undergrads wrote for them. The origin of this "1/3rd" value appears to be this 1936 paper by Ferguson (1936) or the later Roughton (1964)  where it formed the conclusion of experiments performed using free haemoglobin solution (rather than 2,3-DPG containing whole red cells). The latter was a part of the hugely influential Handbook of Physiology series on respiratory physiology, edited by Fenn and Rahn, and is therefore the likely influence for generations of subsequent textbook chapters. The failure to account for the presence of 2,3-DPG, Geers & Gros contend, is responsible for this overestimate (as the 2,3-DPG competes for the same binding sites as CO2, and in its presence CO2 carriage by carbamino compounds would be reduced).

Anyway. In the arterial bloodstream, the carbamate CO2-protein complexes and the dissolved CO2 usually account for less than 15% of the total plasma CO2 carriage capacity. The rest is composed of HCO3-. Inside erythrocytes, where the haemoglobin concentration is around 330g/L, the amount of carbamate compounds is greatest, but bicarbonate remains the major player. As exercise increases the amount of CO2 produced by the tissues, the proportion of dissolved CO2 gas in both plasma and erythrocytes increases (triples!) but this increase in dissolved gas has a minor effect on the total blood CO2 content.

In short, in human whole blood CO2 is transported mainly by being converted into bicarbonate. An even more effective way to represent this can be borrowed from Nunn's Respiratory Physiology. In Chapter 10 of the 8th edition (which is all about carbon dioxide transport) a diagram exists which illustrates the change in CO2 transport as plotted against CO2 partial pressure. It is also probably the diagram asked for in the college comments for Question 13 from the first paper of 2015, where the examiners mentioned that "a diagram of pCO2 v CO2 content was helpful".  It closely resembles this:

plot of pco2 vs hco3 blood concentrations

This is in fact the CO2 dissociation curve, similar to to the oxygen-haemoglobin dissociation curve but distinct because unlike oxygen, CO2 is transported in three different ways. As one can plainly see, with increasing pCO2 the bicarbonate concentration changes the most, the dissolved CO2 increases modestly in a linear fashion, and the carbamate content barely changes at all.

CO2 transport as a dissolved gas

CO2 happens to be one of the gases which enjoy a relatively good water solubility. For every 1 mmHg of CO2 about 0.03 mmol/L enters solution. This relationship is reasonably linear over a survivable range of pressures and temperatures.

solubility of CO2 in water

In solution, CO2 will reversibly combine with water to form carbonic acid, but it does so with great reluctance. One can describe this reluctance mathematically, and express it as a hydration equilibrium constant (Henry's constant). This constant is derived by dividing the concentration of H2CO3 by the concentration of aqueous CO2. Thus, at 25°C Henry's constant for COis only around 1.7 x10-3, which means that in any given jar of water, the majority of dissolved CO2 remains as a dissolved gas, and only a tiny fraction (0.17%) is present as H2CO3.

Anyway. The total dissolved CO2 content of blood can be calculated from the abovestated relationship ( 0.03mmol/L/mmHg); it is therefore 1.2mmol/L. 

CO2 transport as bicarbonate

Conversion of CO2 to carbonic acid and bicarbonate

The combination of CO2 and H2O leads to the formation of H2CO3 by an entirely spontaneous uncatalysed manner. CO2 acts as a Lewis acid in this setting; having no protons to donate it instead acts as "something capable of forming a covalent bond with an electron pair".

The spontaneous reaction with water is actually rather sluggish. For clinically significant amounts of CO2 the uncatalysed dissociation reaction CO2 + H2O ⇌ H2CO3 can take about 3-4 seconds to half-equilibrate, and up to a minute to reach complete equilibrium (and that is in the steamy reaction-supporting body temperature, 37°C). Obviously that is far too slow. There would not be enough time for this reaction to run to equilibrium during the rapid transit of red cells through the gas exchanging pulmonary capillaries, and CO2 removal would not occur.

conversion of CO2 and H2O into carbonic acid

Fortunately, the insides of erythrocytes (as well as the walls of blood vessles) are packed full of carbonic anhydrase (specifically CA type II) , which is perhaps the most rapidly acting enzyme in the human body, and with the aid of which this reaction progresses 25,000 times faster, reaching 95% completion within 2 milliseconds. In the macro-scales of ventilation, measured in seconds and minutes, this reaction can be viewed as essentially instantaneous. Because of this sort of catalytic support, the conversion of HCO3- and H+ back into CO2 and H2O can occur in the pulmonary capillaries during the very brief pulmonary capillary transit time.

In fact, so efficient is carbonic anhydrase, that relatively few enzyme molecules are required to sustain a completely normal level of CO2 exchange. It would appear that one requires perhaps as little as 2% of unblocked enzyme to carry on. Consider that this enzyme system is routinely blocked for therapeutic reasons by drugs such as acetazolamide. Indeed, massive overdoses of carbonic anhydrase inhibitors have been surprisingly survivable, in spite of the severe metabolic acidosis which occasionally ensues.

CO2 transport as carbamate compounds

Carbamate compounds are the dissociated conjugate bases of carbamino acids, which form in the spontaneous reaction of R-NH2 and CO2.

formation and dissociation of carbamate compounds

Thus, a "carbamate" is a conjugate base which acts as a storage device for CO2, and may contribute up to 14% of the total CO2 carrying capacity of the blood. The transitional "carbamino" stage depicted above is - like carbonic acid- a figure of speech rather than a proper macroscopic member of the bloodstream. At physiological pH it dissociates into carbamate and H+ so fast and so completely that its concentration is negligible, and for all intents and purposes it can be

The carbamate content of the plasma is rather poor because serum proteins (eg. globulins) have little interest in transporting CO2, and tend to form carbamates with the greatest reluctance. CO2 can really only bind to side chains of lysine and arginine, and any random plasma protein may only have one of these side chains exposed and available for CO2 binding. More binding sites are available within the red blood cells, where haemoglobin (especially deoxyhaemoglobin) is available in a high concentration.

This paucity of binding sites might make one think that carbamates don't play much of a role in the transport of CO2 in general, and specifically its transport in plasma. Indeed, the carbamates contribute relatively little to the overall CO2 carrying capacity of the human blood. Their importance becomes much greater if for whatever reason most of your carbonic anhydrase is disabled. In that case, suddenly this forgotten transport system becomes very relevant, as it can work with raw CO2and does not require H2CO3 as an intermediate. Moreover, the carbamate system makes the greatest contribution to the difference between arterial and venous CO2 concentration, mainly because of the Haldane effect which is discussed elsewhere.

Factors which influence the CO2 carrying capacity of proteins

CO2 transport as carbamates is influenced by the following factors:

  • Oxygenation of haemoglobin (more deoxygenated= higher CO2 capacity)
  • pH in the local environment (lower pH = higher CO2 capacity)

Inside the red cells, CO2 binds readily to amino acid side-chains of the haemoglobin molecule, particularly when it is deoxygenated. Indeed deoxyhaemoglobin has about 3.5 times the affinity for CO2 when compared to oxyhaemoglobin; this hypoxia-induced increase in CO2 carrying capacity is called the Haldane effect. This is exactly what you want in exercising tissue, which has just consumed all the oxygen in its local blood volume, and has produced a vast amount of CO2. Thus, the carbamate content of venous blood could potentially (at an SvO2 of 0%) be about triple the carbamate content of arterial blood. Of course in reality, the a-v difference is never that great, because venous blood is never that hypoxic.

The presence of carbamate groups in critical regions of the haemoglobin molecule tends to stabilise the deoxygenated form, which decreases the affinity of haemoglobin-oxygen binding. This effect (the Bohr effect) is discussed in greater detail together with the other factors which affect the affinity of haemoglobin for oxygen. Suffice to say the presence of a large amount of CO2 decreases this affinity and promotes the release of more oxygen from haemoglobin, which again is precisely what is needed in exercising tissue.


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