Authors: Nigel Harrison, Peter Driscoll, Carl Gwinnutt / Editors: Jason Kendall / Reviewer: Phil Delbridge / Codes: CP2, ResP2, RP5, SLO1, SLO3 / Published: 11/08/2022
The purpose of this session is to familiarise you with the movement of oxygen from the external environment to the mitochondria where it is required for cellular metabolism.
The factors that may reduce oxygen levels at the tissues must be understood to enable appropriate interventions to be implemented in the emergency department (ED).
The Respiratory Cycle
In a normal unforced breath approximately 500 ml (7-10 ml/kg) of inspired air is directed via the nares, where humidification, warming and filtration transpire, to the oropharynx and thence to the trachea via the laryngeal inlet.
From here the air traverses the main stem bronchi and is propelled to the bronchioles and terminal bronchioles. These three areas, with the trachea, constitute the conducting zone. There are 23 divisions of the bronchio-alveolar tree of which the first 16 constitute the conducting zone. From the conducting zone (CZ) the air is carried to the transitional zones (TZ) and respiratory zones (RZ) where gas exchange occurs.
Within the respiratory tree the areas where gas exchange does not occur (usually the CZ) are referred to as the anatomical dead space.
In contrast an area of the TZ and RZ receiving little or no blood is referred to as alveolar dead space. Together these make up the physiological deadspace i.e. the total volume of the respiratory tract that is not functionally involved in gaseous exchange.
Of the 500ml in the normal tidal volume, 150ml occupy the anatomic dead space so permitting 350ml to participate in gas exchange.
The percentage of a gas in a mixture does not accurately convey the quantity of the gas present. For example, oxygen has the same percentage at sea level and at the top of Mount Everest, but in the latter case the actual quantity of oxygen is much lower. Therefore, we use the partial pressure (P) of a gas as a surrogate measure of the number of molecules.
The partial pressure of a gas is a measure of the concentration of the gas in the medium or tissue in which it exists e.g. arterial blood or air.
Each gas in a mixed gas environment produces its own partial pressure with the result that the sum of the pressures of the different gases provides the total pressure created by the mixture. This is defined in Dalton’s law of partial pressure.
The pressure of a mixture of gases is equal to the sum of the pressures of all of the constituent gases alone.
Mathematically PTotal = P1 + P2 … Pn
Total pressure of dry air = Pressure of (nitrogen + oxygen + carbon dioxide + inert gases).
The partial pressure of any particular gas in a mixture can be calculated by multiplying the percentage of the gas by the total pressure of the mixture.
For example, the partial pressure of oxygen in dry air at sea level is:
21% x 101(kPa) = 21/100 x 101 = 21.2 kPa
In order to avoid confusion it is important to indicate the medium/tissue in which the partial pressure of the gas was measured. This is written as Pmedium.
The following represent(s) the partial pressure of oxygen in a given medium/tissue:
PO2 is the partial pressure of oxygen in the atmosphere.
PAO2 is the partial pressure of oxygen in the alveoli.
PaO2 is the partial pressure of oxygen in arterial blood.
PvO2 is the partial pressure of oxygen in venous blood.
For tissues to survive, oxygen has to be delivered to them from the atmosphere. This is achieved by the respiratory and cardiovascular systems working together so that a specific sequence of events can take place:
- Oxygen delivery to the lungs
- Transfer of oxygen into the blood
- Oxygen carriage by the blood
- Oxygen delivery to the tissues
- Release of oxygen to the tissues
Oxygen will only pass from the atmosphere, to blood, to tissues, if it moves from a relatively high concentration to a lower one. Consequently there is a gradual fall in the partial pressure of oxygen in the different phases of the sequence.
This is referred to as the oxygen cascade.
|Mean partial (kPa) pressureÂ of oxygen
Impairment of any of these processes can lead to hypoxaemia (a low level of oxygen in the blood). A break at any point in this sequence will lead to a deficiency in tissue oxygenation and this is called hypoxia.
The Oxygen Cascade
|Mean partial pressure of oxygen
You will see from Table 1 that there is a drop of almost one-third in the partial pressure of oxygen between the atmosphere and the alveoli. There are several reasons for this. Try to list three reasons in the space below.
In the normal dry atmosphere oxygen (O2) constitutes 21% by volume of the constituent gases.
Saturation of air with water vapour. Water vapour has its own partial pressure (PH20, 6.3 kPa), this reduces the total partial pressure for all the other gases to 101 – 6.3 = 94.7 kPa. The gases are still present in their original percentages but their partial pressure is reduced. The partial pressure of inspired oxygen is now 94.7 x 0.21 = 19.9 kPa. (This can be expressed as: PiO2 = FiO2 x [PB-PH2O]).
The addition of carbon dioxide (CO2) to the gas in the alveoli. Oxygen is removed from alveolar gas and replaced with CO2 (nitrogen is unaffected). The partial pressure of CO2 is around 5.3 kPa, thereby further reducing the partial pressure of O2 to 14.6 kPa (19.9 – 5.3 = 14.6 kPa).
Additionally there is a continual uptake of alveolar oxygen by the blood and replacement by the arrival of fresh gas.
The process of moving air into and out of the lungs is called ventilation. The amount of the inspired air which reaches the alveoli so that it is available for gas exchange is called the alveolar ventilation. The amount of oxygen reaching the lungs is dependent upon:
The partial pressure of oxygen in the inspired gas
Alveolar Gas Equation (AGE)
The O2 level at the alveolus i.e. the partial pressure at the alveolus (PA) can be calculated by using the AGE.
PAO2 = PiO2 – PACO2/R
- PiO2 = partial pressure of oxygen in inspired gas
- PACO2 = partial pressure of carbon dioxide in the alveoli
- R = respiratory quotient
The respiratory quotient is the ratio of CO2 production to O2 consumption and depends upon what macronutrients the body is using for fuel (carbohydrate/fat/protein). The respiratory quotient of a mixed diet is around 0.8.
When breathing atmospheric air:
- PAO2 = FiO2 x (PB – PH2O) – PACO2/0.8
- PB = Barometric (atmospheric) pressure
- PACO2 cannot be easily measured and so PaCO2 (as measured by the blood gas machine) is used as the two values are virtually identical
PAO2 = 0.21 x (101-6.3) – PaCO2/0.8
PAO2 = 19.9 – (5.3/0.8) = 13.3kPa
The respiratory quotient may equal 1 in a carbohydrate enriched diet which would render the AGE: PAO2 = 95 x FIO2(%) – PaCO2.
The amount of gas reaching the alveoli
Alveolar partial pressure
Increasing or decreasing the amount of oxygen in the inspired gas causes the alveolar partial pressure to change in the same direction but not necessarily by the same amounts.
Consider what happens to the PAO2 when the inspired gas is changed from room air (21%) to 40% oxygen.
The PAO2 when inspiring room air:
= [95 x 21%] – [1.25 x 5.3] = 13.3 kPa
And the PAO2 with an inspired oxygen concentration of 40%:
= [95 x 40%] – [1.25 x 5.3] = 31.3 kPa
Compare this increase to the fall in PAO2 which occurs when the inspired oxygen concentration is reduced to 15%:
= [95 x 15%] – [1.25 x 5.3] = 7.6 kPa
The fall in PAO2 following a reduction in inspired oxygen concentration is greater than the rise in PAO2 following the same increase in inspired oxygen concentration.
The second example demonstrates that by almost doubling the inspired oxygen percentage to 40%, we have more than doubled the normal PAO2.
In contrast, by reducing the inspired oxygen percentage by only a quarter to 15%, the PAO2 has nearly halved. The reason for this disproportionate effect is because the partial pressure of carbon dioxide and saturated water vapour pressure in the alveoli remains the same.
Ventilation and Perfusion
When the rate and depth of ventilation is reduced (hypoventilation), less oxygen is delivered per minute to the alveoli to replace that taken up by the blood. This causes the partial pressure of oxygen within the alveoli to fall. Hypoventilation may be mitigated by increasing the concentration of oxygen in the inspired gas.
Hypoventilation always reduces PAO2 unless there is an increase in the inspired oxygen concentration sufficient to compensate.
What happens if hypoventilation persists?
A point will eventually be reached where compensation is no longer possible. For any subsequent reduction in inspired concentration, the PAO2 will fall precipitously.
If the alveolar capillary suffers impaired delivery of blood, as occurs in pulmonary embolism, the situation is referred to as hypoperfusion.
Further information on ventilation/perfusion (V/Q) mismatch
Under normal conditions, ventilation (V, 5 l/min) and perfusion (Q, 5 l/min) are well matched (despite minor variations at the extremes of the apices and bases) and the ventilation/perfusion ratio is approximately 1. If ventilation exceeds perfusion, for example in shock (low cardiac output, V/Q>1), there is not enough haemoglobin circulating to accept all the oxygen available with any consequent increase coming form O2 going into solution which is marginal.
Conversely, when perfusion exceeds ventilation – for example a lung contusion or pneumonia (reduced ventilation, V/Q <1) – there is an inadequate amount of oxygen to fully saturate the haemoglobin. The reduced oxygen in the blood leaving these areas of the lung has the same effect as “shunting”. Areas of normal, high and low V/Q can co-exist in the injured or infected lung. Consequently the final oxygen content of arterial blood depends upon the combined influence of all three. Areas of high V/Q cannot compensate for areas of low V/Q. As the latter tends to predominate hypoxaemia occurs. Unsurprisingly, V/Q mismatch is responsible for many deaths in trauma victims.
Once 30% or more of the blood in the pulmonary circulation passes through an area of low V/Q, the hypoxia cannot be corrected by simply increasing the oxygen content of the inspired gas.
From the alveolus, oxygen diffuses across the respiratory membrane to the erythrocyte (RBC) traversing the capillary. This membrane has an average thickness of 0.5 µm. Movement across the alveolar membrane is termed diffusion.
The rate at which this occurs is affected mainly by the following:
- The surface area of the membrane
- Membrane thickness
- The partial pressure gradient of the gas
- The solubility of the gas in blood
The governing laws are:
Fick’s law of diffusion governs this behavior of gases.
The net diffusion rate (DR) of a gas across a fluid membrane depends upon a temperature-dependent diffusion constant (K), and is proportional to the difference in partial pressure (P2 – P1), proportional to the area of the membrane (A) and inversely proportional to the thickness of the membrane (d).
Mathematically DR = KA(P2 – P1)/d
The anatomy of the lung is ideally suited for the migration of gases either from the alveoli to the blood or in the reverse direction. The alveolar membrane is approximately 100m2 and is only 0.5μm thin. This is especially helpful to mitigate the poor solubility of O2 in blood.
Under normal circumstances, the combination of all the factors affecting gas transfer will enable the RBCs in the pulmonary capillaries to collect their maximum limit of oxygen in less than 0.25 seconds. As the time taken by red cells to travel along the pulmonary capillaries is about 0.75 seconds in a resting healthy adult, there is normally a great deal of diffusion reserves. However, high cardiac output states may shorten the capillary transit time sufficiently to cause hypoxia.
At a constant temperature, the amount of a particular gas dissolved (C) in a given type and volume of liquid is directly proportional to the partial pressure (P) of that gas in equilibrium with that liquid.
Mathematically P = kC
At most, 2% of the transported O2 is in solution. Henry’s law dictates this insignificant quantity of O2 dissolved in plasma. It will be noted that increasing the partial pressure will permit greater gas quantities to be dissolved and the advent of hyperbaric therapy takes advantage of this law.
There is, however, a limit of tolerance of pressures to which a patient may be subjected.
If the oxygen carrying ability of blood relied only upon how much could be dissolved in plasma, our tissues would not survive. The reason being only 3 ml of oxygen dissolves in every litre of blood in a patient breathing room air at sea level. With a normal cardiac output of 5 L/min, this would result in the delivery of 15 ml O2 per minute to the tissues. As the normal resting demand for oxygen is 250 ml/min, this is clearly inadequate. Therefore a system is needed to increase the oxygen carrying capacity of blood so that the delivery of oxygen to the tissues can be improved. This extra help is provided by the presence of red cell Haemoglobin (Hb). Each molecule can carry four molecules of oxygen and there is an average concentration of 150 g/L blood.
Haemoglobin transports 98% of oxygen in the blood.
Quaternary function of oxygen
O2already attached to haemoglobin helps the uptake of further oxygen molecules:
When haemoglobin is fully saturated with oxygen it is called oxygenated haemoglobin (or oxyhaemoglobin) and when deoxygenated it is called deoxyhaemoglobin.
When deoxyhaemoglobin is exposed to oxygen, the uptake of each molecule of oxygen facilitates the uptake of the remainder (a property referred to as the quaternary function of haemoglobin). This process occurs in less than 0.01 seconds and is called association. The opposite of this, i.e. the off-loading of oxygen, is known as dissociation.
It is the presence of haemoglobin that permits sufficient O2 to be transported to tissues. Due to the high PO2 at the alveolus there is ready transfer of O2 to the RBC across the pressure gradient. Once all the haemoglobin molecules have taken up four oxygen molecules, the haemoglobin is said to be 100% saturated.
This is often expressed as SaO2 = 100%, whereÂ Â Â S = saturation and a = arterial.
When the SaO2 = 100%, each gram of haemoglobin in the arterial system is carrying 1.34 ml oxygen – a figure known as the oxygen carrying capacity of haemoglobin (OCC Hb).
Consequently each litre of arterial blood, containing 150 g haemoglobin, will carry 150 x 1.34 = 201 ml oxygen. Compare this to the 3 ml of oxygen which would be carried if the oxygen was merely dissolved in the blood.
Learning bite The presence of haemoglobin allows nearly seventy times more oxygen to be carried than would be possible if blood relied simply on oxygen dissolved in the plasma.
A saturation of 100% is only achieved if haemoglobin is exposed to a PO2 of 33.2 kPa. If it is exposed to a lower partial pressure, the percentage falls. This can be represented graphically to produce a curve .
The rapid uptake of oxygen is represented by the initial steep slope of the curve, where small changes in PaO2 cause large changes in the saturation. Beyond a PO2 of 6.6 to 8.0 kPa, the curve becomes flatter as little further saturation occurs despite increases in PO2. In the normal situation a PaO2 of approximately 13.3 kPa results in a saturation of around 97%.
This curve is called the oxyhaemoglobin dissociation curve, although it clearly relates also to the association of oxygen with haemoglobin.
As we have seen, the total volume of oxygen carried in arterial blood at any time is the sum of that carried by the haemoglobin (98%) plus that dissolved in the plasma (2%). This total is termed the arterial oxygen content.
The oxygen content is dependent upon:
- ⦁ The haemoglobin concentration [Hb] in the blood
- ⦁ The oxygen carrying capacity of the haemoglobin OCC Hb
- ⦁ The saturation of haemoglobin with oxygen SaO2 (Hb)
- The oxygen dissolved in the plasma
The volume of oxygen dissolved in plasma from arterial blood is directly proportional to the PaO2 and is approximately: 0.23 ml per litre blood per kPa PaO2.
Arterial oxygen content = ([Hb] x OCC Hb x SaO2(Hb)) + (0.23 x PaO2)
Increasing the PaO2 above 10kPa has a major effect on increasing the volume of oxygen dissolved in the plasma.
Decreasing the PaO2 leads mainly to a reduction in the volume of oxygen carried by haemoglobin.
Even at a low PaO2 there is still a considerable amount of oxygen in the blood which can act as an oxygen reserve.
Under normal circumstances
- The haemoglobin concentration = approximately 130-165 g/l in men, 115-150 g/l in women
- The oxygen carrying capacity of Hb = 1.34 ml/g
- The SaO2 = 97%
- The volume of oxygen dissolved in plasma = 0.23 ml/l/kPa
It follows that the oxygen content per litre of arterial blood (i.e. the amount associated with the haemoglobin molecule as well as that dissolved in the plasma) is equal to:
[Hb] x OCC Hb x SaO2(Hb) + 0.23 x PaO2
Oxygen content of haemoglobin + Oxygen content of the plasma.
Consider a person who has a PaO2 of 10 kPa with a [Hb] of 150 g/L which is 97% saturated with oxygen. What will the oxygen content per litre of arterial blood be in this person?
It will be equal to:
(150 x 1.34 x 97%) + (0.23 x 10)
= 195 + 2.3
≈ 197 ml
Now consider if the inspired oxygen is increased such that the PaO2 is 50 kPa. This will result in the Hb being 100% saturated. What will the oxygen content be in this case?
It will be:
(150 x 1.34 x 100%) + (0.23 x 50)
= 201 + 11.5
= 212.5 ml/L blood
Now consider if the inspired oxygen is reduced to 4.5 kPa, resulting in the haemoglobin being 57% saturated. What will the oxygen content per litre of blood be in this case?
It will be:
(150 x 1.34 x 57%) + (0.23 x 4.5)
= 115 + 1.03
= 116 ml/L blood
A-a Oxygen Gradient
The alveolar gas equation allows calculation of the alveolar O2 tension (PAO2).
PAO2 = (PB – PH2O) x FiO2 – (PaCO2/0.8)
PAO2 = 95 x FiO2 – (PaCO2/0.8)
Under normal circumstances the difference between this and the arterial O2 tension (PaO2) measured by the ABG machine is 2-4 kPa. This difference is known as the A-a gradient. Its calculation can help to distinguish between types of hypoxia.
In cases of multiple or large pulmonary emboli the A-a gradient is usually increased.
The PAO2 may be easily estimated for FIO2> 30% by subtracting 13 from the FIO2.
The total volume of oxygen delivered to tissues per minute is the product of the cardiac output and the oxygen content:
Oxygen delivery (DO2) = cardiac output x oxygen content.
In normal circumstances, cardiac output is about 5000 ml/min. Therefore:
DO2 = 5000 ml/min x 197 ml/litre
≈ 1000 ml/min (since circulating volume of blood is around 5000 ml).
This value will clearly be affected by changes in the cardiac output and oxygen content, either separately or in combination. In practice, increases in oxygen delivery are mainly achieved by augmenting the cardiac output (e.g. during exercise) because the potential for further increases in the oxygen content is small. As we have seen in the previous example, this is the case even if the inspired concentration is increased significantly.
Larger effects on the delivery of oxygen can occur if either value falls. For example, there is a reduction in the amount of oxygen which could be carried by each litre of blood in patients with anaemia. Although this would cause the DO2 to fall, the reduction would be limited by the body increasing the cardiac output as a means of compensation.
A life-threatening fall in oxygen delivery can occur when both the cardiac output and the oxygen capacity is reduced, as occurs in a trauma patient who has lost 30% of his blood volume. The reduced circulating blood volume both reduces the cardiac output and the oxygen carrying capacity. A state of high oxygen demand usually drives an increased cardiac output to furnish the additional O2, but augmented O2 extraction may supervene if the quantity delivered is insufficient.
1g of Hb carries 1.34 ml of O2 if fully saturated. With a PO2 of 13.3 kPa Hb is normally about 97% saturated and at a Hb concentration of 150 g/L arterial blood will hold ≈ 200 ml/L of O2. Therefore with a cardiac output of 5/Lmin, the O2 in the circulation is 1 L/min.
When arterial blood arrives at the tissues, it enters an environment where the partial pressure of oxygen is much lower. Consequently, despite the affinity of haemoglobin for oxygen, there is movement of oxygen molecules from haemoglobin through the plasma and into the tissues, down the partial pressure gradient.
Under normal circumstances however, not all of the oxygen is removed from the blood passing through the tissues.
For example, at rest the body’s requirement for oxygen is approximately 250 ml per minute. However as the total volume of oxygen available at any time is 1000 ml, only 25% of available oxygen is removed from the haemoglobin. Therefore venous blood is still 75% saturated, even though the partial pressure of oxygen has fallen to just 5.3 kPa. This represents another reserve which allows the body to adapt to conditions where the oxygen demand is increased e.g. during exercise or illness.
The oxygen content of venous blood can be calculated as follows:
= (Hb x 1.34 x SvO2) + (0.23 x PvO2)
= (150 x 1.34 x 75) + (0.23 x 5.3)
= 150.8 + 1.2
= 153 ml/L
The release of oxygen from haemoglobin to the tissues is facilitated by the steep lower part of the haemoglobin dissociation curve. This enables large amounts of oxygen to be released from the blood for only a small drop in the partial pressure of oxygen in the capillaries.
A variety of local factors can also affect the ability (or affinity) of the haemoglobin molecules to carry oxygen whilst they circulate in the capillaries perfusing the tissues.
The most important of these factors is the acidosis in the tissues as a result of their metabolic activity. This local fall in the pH (rise in H+) has the effect of ‘shifting’ the haemoglobin dissociation curve to the right of its position in the graph i.e. for a given partial pressure of arterial oxygen the saturation is less. This means that more oxygen is released in close proximity to the tissues, which require it.
The graph illustrates the effect of ph changes on the O2Hb dissociation curve.
The same effect is seen with increases in:
Partial pressure of CO2
Tissue Factors Continued
As active muscles exhibit all these features, the delivery of oxygen to them is greatly assisted. Also 2,3-DPG is generated during metabolism, so is at a higher concentration at the peripheral tissues.
The graph illustrates the effects of 2,3-DPG levels on the O2Hb curve.
By preferentially binding to deoxyhaemoglobin, it stabilises the reduced state Hb, making it harder for O2 to bind Hb and more likely to be surrendered to adjacent tissues.
The above processes produce a rightward shift of the curve. The shift in the oxygen dissociation curve as a result of changes in PaCO2 is known as the Bohr Effect. At the alveolar level the reverse enables O2 to saturate the RBCs and thus perpetuate the cycle.
An indication of the amount of shift of the oxygen dissociation curve can be gained from checking the P50.
This is the partial pressure of oxygen required to saturate 50% of the haemoglobin. It is normally around 3.6 kPa and is often provided with the blood gas result.
The graph illustrates the differences between adult and fetal haemoglobin.
A rise in PaCO2, hydrogen ions and temperature shifts the haemoglobin dissociation curve to the right. A rise in the P50 indicates a shift in the haemoglobin dissociation curve to the right. A fall in the P50 indicates a shift in the haemoglobin dissociation curve to the left.
Types of Hypoxia
Diminished delivery of O2 to the alveolar capillaries is termed hypoxic hypoxia and may occur at high altitude with decreased PO2 but you are more likely to see it in your ED in patients with COPD, reduced ventilation and those with right-to-left shunts leading to significant intermixing of venous and arterial blood.
COHb absorbs roughly the same wavelength of light as oxy Hb. Pulse oximeters therefore overestimate true SaO2 with the degree of overestimation proportional to the level of COHb.
- Anaemic hypoxia: Hb concentration is insufficient to transfer sufficient O2
- Ischaemic or stagnant hypoxia: Circulatory failure prevents normally oxygenated blood being delivered to the tissues
- Histotoxic hypoxia: Disablement of oxidative phosphorylation enzymes in the mitochondria
Fetal Hb (HbF)
HbF causes a left shift of the oxy Hb curve, as its P50 is 2.5 kPa vs a P50 of 4.0 kPa for adult Hb. This results from the reduced interaction with 2,3-DPG (adult Hb binds O2 more avidly in the absence of 2,3-DPG). Additionally HbF exists at a higher concentration of 180 g/L to augment oxygenation.
MHb is the oxidized Fe3+ form of Hb and lacks the electron needed to permit O2 binding, thus is incapable of oxygen transport. Due to continuous exposure of RBCs to various oxidant stresses, blood normally contains approximately = 1% MHb levels.
When approximately 50 g/L of Hb is at least 85-90% saturated i.e. deoxygenated, cyanosis occurs giving a dark blue colour to the skin. Consequently patients who are moderately to severely anaemic may be hypoxaemic without being cyanotic.
MHb level is kept in check by the enzyme MHb reductase (cytochrome b5 reductase) which returns the Fe3+ to the Fe2+ state. This enzyme may be congenitally absent or oxidizing drugs and chemicals may overwhelm its function.
Substances with the potential to cause methaemoglobinaemia include:
- Sulphonamide antibiotics (eg. Trimethoprim, Dapsone)
- Local anaesthetics (eg. Lignocaine/Prilocaine)
- Aniline (found in many industrial chemicals)
- Chlorates, Bromates & Nitrates (found in fertilisers, pesticides)
Treatment of methaemoglobinaemia is with methylene blue.
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