The Haldane Effect

This chapter is most relevant to Section F8(ii) from the 2023 CICM Primary Syllabus, which expects the exam candidates to be able to "describe the carbon dioxide carriage in blood". The Haldane effect is not mentioned in the syllabus, but surely it must be implied, as one cannot have any discussion of CO2 transport without it. Though nobody has ever asked a CICM SAQ using the phrase "what is the Haldane effect?" it is clearly a fair question and people should expect to know this for this exam. Like most sane people, Haldane did not refer to this thing as "my Effect", though he could have clearly done so with minimal false modesty because it was in fact Haldane's own defibrinated blood that was used for the experiment.

In summary: 

  • The Haldane effect is a physicochemical phenomenon which describes the increased capacity of blood to carry CO2 under conditions of decreased haemoglobin oxygen saturation
    • Both Haldane and Bohr effects are the same features of the same phenomenon
    • Haldane effect is what happens to pH and CO2 binding because of oxygen, and Bohr effect is what happens to oxygen binding because of CO2 and lower pH. 
  • More CO2 binds to haemoglobin at lower oxygen saturation
    • This effect facilitates the removal of CO2 from the tissues
  • Bound CO2 is released from haemoglobin when it becomes oxygenated
    • This "reverse Haldane effect" facilitates the elimination of CO2
  • There are two mechanisms:
    • Deoxygenated haemoglobin has a higher affinity for CO2
      • This is due to the allosteric modulation of CO2-binding sites by the oxygenated haem
    • The buffering capacity of deoxygenated haemoglobin is increased; 
      • Reduced (deoxygenated) haemoglobin becomes more basic
      • This increases the pH of the RBC cytosol
      • With an increased pH, more carbonic acid may dissociate into bicarbonate
      • Thus, the total amount of CO2 carried as bicarbonate is increased
      • Compared to the carriage of CO2 by deoxyhaemoglobin, this part of the Haldane effect plays a minor role

Tebboul & Scheeren (2017) offer a no-frills defatted explanation, and their article is available for free. If one wants fat and frills, one can go to this excellent review by Itiro Tyuma (1984). Though is not essential, one may also wish to read J.S Haldane's original article, where he was the third author (Christiansen et al, 1914).

Definition of the Haldane effect

There is no formal definition here, but fortunately virtually every author who has ever written on the subject has felt the need to preface their article with some introductory words, where they inevitably make an attempt to define this phenomenon, or at least to so pithily summarise it that it is covered by a single sentence. A representative definition, therefore, might be:

"The Haldane effect is a physicochemical phenomenon which describes the increased capacity of blood to carry CO2 under conditions of decreased haemoglobin saturation"

Or something like that. In reality, the Haldane effect and the Bohr effect are different expressions of the same molecular mechanism which is somewhat unrelated to CO2 (that just happens to be the ligand of interest in respiratory physiology). Realistically, there are numerous other molecular actors (protons, inorganic ions such as chloride, organic phosphates such as 2,3-DPG) which bind to deoxygenated haemoglobin with a higher affinity. At the same time, the action of binding these various molecules tends to stabilise the deoxygenated T-state of the haemoglobin molecule, decreasing its affinity for oxygen (which is basically the Bohr effect). Thus, if one were faithful to the facts, one would be forced to admit that both effects should really have the same definition:

  "The Bohr-Haldane effect is a physicochemical phenomenon which describes the changes in affinity for nonoxygen ligand binding by haemoglobin which result from the conformal changes induced in the haemoglobin tetramer by the binding of oxygen to haem"

However, that does not exactly roll off the tongue. Nor would anybody among the CICM examiner population be particularly upset if one prefers the previously mentioned carboxy-centric definition. Haldane and Bohr effects are generally separated in the college literature. Also,  historically exam-oriented study guides such as Brandis' The Physiology Viva tend to discuss them as separate phenomena, probably because their clinical relevance is somewhat different. In any case, one would probably do well if one were to just quote Nunn's:

"[The Haldane effect is] the difference in the quantity of carbon dioxide carried, at constant PCO2, in oxygenated and deoxygenated blood"

Haldane effect due to CO2 carriage by deoxygenated haemoglobin

The fact that CO2 can bind to amino acids to form carbamino acids and carbamate conjugate bases has already been discussed elsewhere. The question is, what makes red cell haemoglobin so special, and how does this change when haemoglobin is oxygenated? 

In short:

  • CO2 binds to uncharged N-terminal α-amino groups on both α and β subunits of haemoglobin
  • Oxygenation of the haem iron atom in a haemoglobin molecule is a heterotropic allosteric modulator of these CO2 binding sites because it introduces a conformational change to the haemoglobin tetramer (positive cooperativity)
  • As the result of this allosteric modulation, CO2 has a higher affinity for the deoxygenated T state than for the R-state
  • This mechanism contributes 70% of the total CO2 carriage due to the Haldane effect (Roughton, 1964), and therefore about 10-15% to the total transport of CO2 in the blood.

That's probably good enough for government work, but if one really wants to submerge into the gurgling swamp of physiological minutiae, Austen Riggs' article from 1988 will serve as an excellent starting point. As mentioned above, the "effect" is not limited to CO2, but rather is a phenomenon that also involves haemoglobin binding promiscuously with various other ion species.  Deoxygenated haemoglobin is a massive whore for protons, for example. The act of completely deoxygenating a volume of blood (down to an SaO2 of 0%) sucks up enough protons to increase the pH of the volume by 0.03, according to Nunn's (p. 155 of the 8th edition). This is a fine way to segue to the next section:

Haldane effect due to increased buffering by haemoglobin

Again, in summary:

  • Each haemoglobin tetramer molecule has 38 charged histidine residues, of which four are attached to the haem group.
  • The dissociation constant for each of these histidine residues is influenced by the oxygenation of the haem
  • As a result, when haem loses oxygen, the haemoglobin tetramer as a whole becomes more basic. 
  • This removes hydrogen ions from solution (i.e. buffers the solution)
  • The effect of this on the equilibrium of bicarbonate and carbonic acid favours the conversion of carbonic acid into bicarbonate
  • Thus, the loss of oxygen from the haemoglobin tetramer, by buffering, increases the amount of CO2 being carried in the form of bicarbonate

This probably contributes only about 30% of the Haldane effect. It also contributes to the pH change in venous blood. Venous blood would ordinarily be quite acidic due to the presence of extra CO2 (6mm Hg more than arterial blood), but the buffering effect of deoxygenated haemoglobin restores its pH closer to normality, so much so that some claim venous samples can safely replace arterial for the measurement of pH among ED patients.

Consequences of the Haldane effect for total CO2 carriage

Again, one is forced to look at this diagram of the carbon dioxide dissociation curve. 

plot of pco2 vs hco3 blood concentrations

Observe that there is a difference between the arterial and venous carbamate content. However, the difference remains fairly stable along the continuum from 10mmHg to 80 mmHg of CO2. It is as if the actual PaCOdoes not matter. That is in fact the case: the difference between arterial and venous carbamate carriage of CO2 is purely due to the difference in the level of haemoglobin oxygenation. Occasionally, one is expected to identify the "arterial point" and "venous point" on these curves, which illustrate how the Haldane effect contributes to the (minor) difference in total CO2 content between arterial and mixed venous blood. In short, though the total difference is minor, the Haldane effect is said to be responsible for more than a third of it. This should be the official position of anybody who is within listening distance of the CICM thought police, and is the likely expected answer for any SAQ on the topic (whereas the reality may be a much lower value, perhaps as low as 5%).

To look at these a little more closely:

The important parts of the CO2 dissociation curve

This diagram, common among textbooks, illustrates that if the oxygen saturation of blood is increased, the partial pressure of COwill also increase because more CO2 will be released from its bound sites. For example, if mixed venous blood (SpO2 = 75%) were to become fully oxygenated, the PCO2 would increase from 46 to 55 mmHg (the total COcontent of the blood would remain the same). To put it another way, the main reason for the relatively modest arteriovenous PCO2 difference is the deoxygenation of haemoglobin, and if venous oxygenation was higher, the venous PCO2 would also be raised.

If one were paying attention, one would note that this phenomenon, if it were to contribute usefully to respiration, should play out over miniscule timeframes, roughly in keeping with the time spent by the red cells in the capillary. If it took any longer than that, one would only get a carbon dioxide enriched arterial circulation out of all this. Fortunately, as the lightly colourised graph from Klocke (1973) demonstrates,  the whole process takes place over tenths of a second:

kinetics of the Haldane effect from Klocke (1973).jpg


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