Oxygen carrying capacity of whole blood

This chapter is relevant to Section F8(i) from the 2017 CICM Primary Syllabus, which expects the exam candidates to be able to "describe the carriage of oxygen in blood". Specifically, it refers to the calculation of the oxygen-carrying capacity of blood. This is a fundamental matter. It has come up several times in the past papers: 

• Question 1 from the first paper of 2016 where it formed half of the answer to the question, "outline the determinants of oxygen delivery to the tissues". 
• Question 1 from the first paper of 2018, which asked about the DO₂
• Question 1 from the second paper of 2012, which asked for a comparison of oxygen and carbon dioxide transport 

In brief,

Dissolved oxygen

Oxygen has terrible water solubility. This is especially true at body temperature.

The solubility constant at 37° is around 0.03ml/L/mmHg, or 0.003 ml/dL/mmHg. Thus, in every litre of maximally oxygen-saturated blood (i.e. at an alveolar O₂ of around 100mmHg ) there is only 3ml/L of dissolved oxygen, whereas there might be about 150-200ml/L of oxygens stored in haemoglobin.

In other terms, only about 1-2% of the total oxygen content is dissolved (though this increases with extreme hypothermia). The remaining 98% are bound to haemoglobin.

Thus, in routine practice the dissolved fraction of oxygen will never be a major player in the intensivist's quest to improve tissue oxygenation. Henceforth it will be largely ignored in the ensuing discussion.

It is, of course, somewhat unfair to say that PO₂ is entirely meaningless. True, oxygen tension and oxygen content are related only by the saturation of haemoglobin. However, where haemoglobin is lacking and where FiO₂ is high (i.e. in the ICU), the PaO₂ can have a substantial effect on the oxygen content by increasing the amount of dissolved oxygen, which is usually overlooked under normal circumstances. On room air and with a haemoglobin of 150, every litre of blood in a normal subject carries about 200ml of oxygen as oxyhaemoglobin and about 3ml of oxygen as dissolved gas.  However, at maximum PaO₂ under normal atmospheric conditions (no A-a gradient and FiO₂ = 100%), there is about 20ml of dissolved oxygen per litre of blood.  If Hb is low (let's say, 60g/L), it is only carrying 80.4 ml/L of oxygen.

Thus, under ICUish conditions, dissolved oxygen could potentially contribute as much as 20% of the total arterial oxygen content.  Legrand et al (2014) were able to demonstrate that this actually manipulates the SvO2 so much that it could change your interpretation of the cardiac output (if you were the sort of person who still does that), eg. from 71% to 84%. Moreover, under some truly exotic conditions, dissolved oxygen could account for the bulk of the oxygen deliver. For example, hyperbaric oxygen therapy springs to mind as a scenario where one is actually relying on dissolved oxygen for tissue oxygenation. Indeed, according to a good NEJM article from 1996, at 3 atmospheres of 100% FiO₂ (or, 300% FiO₂, or an alveolar pO₂ of 2280mmHg if you will) tissue oxygen tension approaches 400mmHg.

BO₂: oxygen carrying capacity of haemoglobin

The potential oxygen-carrying capacity of blood is determined by the total haemoglobin concentration which is measured by the ABG machine (and represented as ctHb). However this measurement incorporates all the various species of haemoglobin, including ones which can never act as vehicles of oxygen transport (eg. carboxyhaemoglobin). Thus, this is not a good measure of actual oxygen-carrying capacity, or BO₂. BO₂ is the maximum amount of Hb-bound O₂ per unit volume of blood; it is expressed in mmol/L or in mL standard temperature and pressure dry (STPD)/L or mL(STPD)/dL.

Thus,

BO₂ ~ ctHb - cdysHb (the concentration of non-oxygen-carrying dyshaemoglobins)

Theoretically, BO₂ = 1.39 mL/g.

It is the maximum capacity; i.e the amount of oxygen which would be present in a volume of blood if all of the effective haemoglobin molecules (ceHb) were 100% saturated.

The influence of dyshaemoglobin species on the measurements of sO₂ and FO₂Hb (and how these values differ) is discussed in the chapter on FO₂Hb (the fraction of oxygenated haemoglobin).

Actual oxygen capacity of haemoglobin

if one searched for the oxygen carrying capacity of haemoglobin, one arrives at a series of different results, ranging from 1.30 to 1.39 g/ml. How could that be, one might ask. Surely, in this enlightened age, we might be able to agree on such a fundamental value as the capacity of haemoglobin for oxygen?

This issue arises due to the disagreement between different forms of haemoglobin measurement, as well as changing methods of measuring its oxygen content. Early studies arrived at the popular 1.34ml/g by measuring haemoglobin and carbon monoxide (with carbon monoxide being a rather good substitute marker for oxygen, because it binds haemoglobin in the same molar concentration). This value remained popular until 1963, when Braunitzer measured the molecular weight of haemoglobin very precisely (he decided it was 64,458.5g) and offered a value of 1.39ml/g as the theoretical maximal capacity.

This 1.39 figure was arrived at by the brutal application of raw German stoichiometry. 1 mole of haemoglobin will bind 4 mole of oxygen, and thus 1/64,458.5th of it (i.e. 1 gram) will bind 4 /64,458.5th of a mole of oxygen. If we assume that oxygen is an ideal gas, one mole of it will occupy 22.4L of volume at standard temperature and pressure; thus, the ideal oxygen-binding capacity of haemoglobin must be (4 × 22.4) ÷ 64458.5, or around 1.39 ml/g.

This figure obviously represents some sort of unachievable ideal; it expects haemoglobin to bind oxygen to the very last molecule. One can be forgiven for wondering what the real capacity might be, at the bedside with the living human organism. In the spirit of this inquiry, I.C Gregory measured the total oxygen capacity of several ex vivo samples, and found the mean to be around 1.306 ml/g. This is probably a more realistic representation of what happens in the living human body. If one takes an informal survey of textbooks, the vast majority of them will quote some numeric compromise between 1.30 and 1.39, with 1.34 being the most often quoted value.

Actual oxygen content in blood

The actual oxygen content of blood is dependent upon the haemoglobin content, and the proportion of haemoglobin which is saturated with oxygen. The exact mechanism of oxygen-haemoglobin binding, and the factors which influence it, are all topics for other chapters.

A reasonably accurate impression of oxygen content of blood can be calculated if one can accurately measure the sO₂, and if one knows the BO₂ which can be calculated from the known fractions of all the various haemoglobin species.

Thus,

O2 content of blood =sO₂ × ceHb × 1.39 mL/g

Quantity of oxygen transported into the tissues

So, at 100% saturation there is about 1.39ml of oxygen per every gram of "good" haemoglobin.

This would suggest that at a Hb of 150 g/L you have about  200ml of O2 in every litre of whole blood. 

The equation usually used to describe the rate of oxygen delivery is as follows:

However, one can see how this could break down completely if one were one of the Blue Fugates, running amok in Appalachia with a methaemoglobin level around 30%. One's [Hb] might be normal or high, but of that [Hb] only a proportion is useful for oxygen transport, and the ABG machine's sO₂ measurement only incorporates the effective haemoglobins (and would thus be normal or near-normal, the left shift considered). The result would be a 30% overestimation of the oxygen content of their blood.

One should make some attempt to exclude these aberrant haemoglobin species from the calculation of oxygen delivery.

Thus, a more accurate representation would resemble this:

Thus, at a Hb of 150g/L, in the absence of weird haemoglobin species, in a well-oxygenated 70kg patient with a PaO₂ of 100 and an sO₂ of 100%, with a normal cardiac output of 5L/min the equation looks like this:

DO₂ = 5 × (1.39 × 150 × 1 + (0.03 × 100))

=  5 × (208.5 + 3)

= 1057.5 ml/min, of which 15ml are dissolved and 1042.5ml are bound to haemoglobin.

Thus, the total rate of O₂ delivery (DO₂) is usually around 15ml/kg/min.

The consequences of having inadequate oxygen-carrying capacity have been explored in the chapter on lactic acidosis resulting from extreme anaemia, and from extreme hypoxia. In brief summary, if one is reasonably healthy, one can compensate to a truly insane degree for a loss of either haematocrit or oxygen saturation. Specifically, the cardiac output is the variable which one needs to manipulate; if there is less oxygen in the blood then pumping it harder and faster is the only solution to maintain the DO₂ within the range compatible with aerobic metabolism.