Overview of Oxygen Carriage in Blood
Oxygen is carried in blood in two forms: dissolved in plasma and bound to haemoglobin. These two mechanisms differ dramatically in their capacity and clinical importance.
Dissolved Oxygen
Oxygen dissolves in plasma obeying Henry's Law, the amount dissolved is directly proportional to the partial pressure of oxygen ($P_{O_2}$).
$$\text{Dissolved } O_2 = 0.003 \text{ mL} \cdot 100\text{mL}^{-1} \cdot \text{mmHg}^{-1}$$
At a normal arterial $P_{O_2}$ of 100 mmHg (13.3 kPa):
$$\text{Dissolved } O_2 = 0.003 \times 100 = 0.3 \text{ mL} \cdot 100\text{mL}^{-1}$$
This is clearly insufficient alone. At a cardiac output of 30 L·min⁻¹ during strenuous exercise, dissolved oxygen would deliver only ~90 mL·min⁻¹, far short of tissue requirements of up to 3000 mL·min⁻¹.
Oxygen Bound to Haemoglobin
Haemoglobin is the primary vehicle for oxygen transport. Each haemoglobin molecule contains four haem groups, each capable of binding one oxygen molecule, allowing each molecule to carry up to four oxygen molecules.
- The Hüfner constant: each gram of haemoglobin can carry 1.39 mL of oxygen when fully saturated
- At a normal haemoglobin concentration of 14-15 g·dL⁻¹, arterial blood contains approximately 20 mL·dL⁻¹ of oxygen bound to haemoglobin
- Venous blood contains approximately 15 mL·dL⁻¹ bound to haemoglobin
| Form | Arterial Blood | Venous Blood |
|---|---|---|
| Dissolved $O_2$ | 0.3 mL·dL⁻¹ | ~0.12 mL·dL⁻¹ |
| Haemoglobin-bound $O_2$ | ~20 mL·dL⁻¹ | ~15 mL·dL⁻¹ |
| Total | ~20.3 mL·dL⁻¹ | ~15.1 mL·dL⁻¹ |
Haemoglobin Structure and Types
Adult haemoglobin (HbA) accounts for >98% of haemoglobin in normal adults, composed of two α-globin and two β-globin chains. The remaining ~2% is HbA₂, in which the two β-chains are replaced by δ-chains.
Foetal haemoglobin (HbF), present in utero and in the first few weeks of life, consists of two α-chains and two γ-chains. HbF has a higher oxygen affinity (left-shifted dissociation curve), facilitating oxygen transfer from maternal blood to the foetus.
Haemoglobin S (HbS) has valine substituted for glutamic acid in the β-chains, producing the pathological sickle cell form.
The Oxyhaemoglobin Dissociation Curve
Shape and Mechanism
The relationship between $P_{O_2}$ and haemoglobin oxygen saturation ($S_{O_2}$) is sigmoid (S-shaped), first described by Bohr in 1904. This shape arises from the cooperative binding kinetics of haemoglobin.
In the deoxygenated (tense) state, haemoglobin has low affinity for oxygen. As each successive oxygen molecule binds, it induces a conformational change that increases the affinity of remaining binding sites, this is cooperative binding or haem-haem interaction.
The four sequential reactions between haemoglobin and oxygen have different dissociation constants (K₁ to K₄). Crucially, the final binding step (K₄) has a forward velocity constant (~6.90) many times higher than the earlier steps (~0.05, 0.04, 0.45), explaining why the last 25% of haemoglobin oxygenation occurs rapidly and also why dissociation of oxyhaemoglobin is slower than its formation.
Key Points on the Curve
| Point | $S_{O_2}$ | $P_{O_2}$ |
|---|---|---|
| Arterial point | 100% | 13.3 kPa (100 mmHg) |
| Mixed venous point | 75% | 5.3 kPa (40 mmHg) |
| $P_{50}$ | 50% | 3.5 kPa (26.3 mmHg) |
The P₅₀ is defined as the $P_{O_2}$ at which haemoglobin is 50% saturated under standard conditions. It quantifies any left or right displacement of the curve.
Mathematical Description
The simplified Kelman equation describes the curve at $P_{O_2}$ values >4 kPa:
$$S_{O_2} = \frac{P_{O_2}^3 + 2.667 \cdot P_{O_2}^2 + 2.667 \cdot P_{O_2}}{P_{O_2}^3 + 2.667 \cdot P_{O_2}^2 + 2.667 \cdot P_{O_2} + 55.47} \times 100$$
This equation (with $P_{O_2}$ in kPa) is automatically computed by modern blood gas analysers.
Factors Affecting the Oxyhaemoglobin Dissociation Curve
The curve can shift left (increased haemoglobin affinity for $O_2$, reduced tissue offloading) or right (decreased affinity, enhanced tissue offloading). P₅₀ changes accordingly.
| Factor | Left Shift (↑ affinity, ↓ P₅₀) | Right Shift (↓ affinity, ↑ P₅₀) |
|---|---|---|
| Temperature | ↓ Temperature | ↑ Temperature |
| pH | ↑ pH (alkalosis) | ↓ pH (acidosis), Bohr effect |
| $P_{CO_2}$ | ↓ $P_{CO_2}$ | ↑ $P_{CO_2}$, Bohr effect |
| 2,3-DPG | ↓ 2,3-DPG | ↑ 2,3-DPG |
| Haemoglobin type | HbF, COHb | HbS (mild) |
The Bohr Effect
The Bohr effect describes the large influence of pH on haemoglobin affinity. In systemic capillaries, $CO_2$ enters the blood, $P_{CO_2}$ rises and pH falls, causing a right shift of the dissociation curve. This facilitates oxygen offloading to metabolically active tissues, a physiologically elegant mechanism.
2,3-Diphosphoglycerate (2,3-DPG)
2,3-DPG is produced in red blood cells (RBCs) during glycolysis and binds to deoxyhaemoglobin, stabilising the low-affinity (tense) conformation and causing a right shift.
- Normal RBC 2,3-DPG: ~5 mmol·L⁻¹
- In anaemia (Hb ~60 g·L⁻¹): 2,3-DPG rises to ~7 mmol·L⁻¹
- This increases P₅₀ from ~3.6 kPa to ~4.0 kPa (27 → 30 mmHg)
Oxygen Stores in Blood
Quantitative Summary
| Compartment | Approximate Store |
|---|---|
| Haemoglobin-bound $O_2$ (arterial) | ~20 mL·dL⁻¹ |
| Haemoglobin-bound $O_2$ (venous) | ~15 mL·dL⁻¹ |
| Dissolved $O_2$ (arterial) | ~0.3 mL·dL⁻¹ |
Oxygen Delivery and Consumption
$$\dot{D}O_2 = CO \times CaO_2$$
$$\dot{D}O_2 = CO \times \left([Hb] \times 1.39 \times S_aO_2 + 0.003 \times P_aO_2\right)$$
- Normal oxygen delivery ($\dot{D}O_2$): ~1000 mL·min⁻¹
- Normal oxygen consumption ($\dot{V}O_2$): ~250 mL·min⁻¹
- Oxygen extraction ratio: $O_2ER = \dot{V}O_2 / \dot{D}O_2 \approx 0.25$ at rest
- The heart has a particularly high $O_2ER$ of 0.6, making it exquisitely sensitive to reductions in oxygen delivery
Abnormal Haemoglobin Forms
Carboxyhaemoglobin (COHb)
Carbon monoxide binds haemoglobin with approximately 300 times greater affinity than oxygen. The consequences are twofold:
- Direct reduction of oxygen-carrying capacity, 20% COHb reduces blood $O_2$ content by ~20%
- COHb causes a left shift of the dissociation curve of remaining oxyhaemoglobin (partly via reduced 2,3-DPG), impairing $O_2$ offloading to tissues
This is in stark contrast to anaemia, where P₅₀ is increased (right shift), partially compensating for reduced carrying capacity by enhancing tissue oxygen unloading.
Carboxyhaemoglobin dissociates extremely slowly compared with oxyhaemoglobin.
Methaemoglobin (MetHb)
When haem iron is oxidised from Fe²⁺ to Fe³⁺, it cannot bind oxygen. Normal physiological metHb reductase systems exist:
| System | Contribution |
|---|---|
| NADH-metHb reductase (via glycolysis) | >2/3 of reducing activity, most important |
| Ascorbic acid (direct chemical reduction) | Minor, slow |
| Glutathione-based enzymes | Small |
| NADPH-dehydrogenase (pentose phosphate pathway) | Reserve, almost no effect physiologically |
Treatment: methylene blue activates NADPH-dehydrogenase, rapidly reducing metHb. Ascorbic acid may also be used.
MetHb causes a left shift of the dissociation curve of remaining functional haemoglobin, further impairing tissue oxygenation.
Foetal Haemoglobin (HbF)
HbF has a left-shifted dissociation curve compared with HbA. This higher oxygen affinity is essential in utero, it allows HbF to extract oxygen from maternal HbA at the placenta.
Myoglobin
Myoglobin is a single-chain oxygen-binding protein in muscle. Its dissociation curve is hyperbolic (not sigmoid, as it lacks cooperative binding). It reaches near-full saturation at $P_{O_2}$ values normally found in voluntary muscle (2-4 kPa, 15-30 mmHg). Most of its oxygen is only released at very low $P_{O_2}$ during intense exercise, functioning as an intracellular oxygen store and facilitating oxygen diffusion within muscle cells.
Clinical Relevance
Pulse Oximetry Limitations
Pulse oximetry measures $S_{pO_2}$, not $P_{aO_2}$. On the flat upper portion of the dissociation curve, large changes in $P_{aO_2}$ produce little change in saturation. A patient may have a $P_{aO_2}$ falling from 13.3 to 8 kPa (100 → 60 mmHg) with $S_{aO_2}$ remaining >90%, masking significant hypoxaemia until the steep part of the curve is reached.
Pulse oximetry cannot distinguish oxyhaemoglobin from carboxyhaemoglobin, $S_{pO_2}$ may read falsely normal in CO poisoning.
Pre-oxygenation Before Induction
The rationale for pre-oxygenation is to maximise the oxygen store in the functional residual capacity (FRC) and, to a lesser extent, in blood. By raising $F_iO_2$ to ~1.0, dissolved oxygen in plasma increases proportionally, but the haemoglobin-bound fraction increases minimally (already >97% saturated at room air breathing). The benefit is primarily from the pulmonary $O_2$ store, though understanding the blood oxygen stores informs the time available before desaturation.
Anaemia and Transfusion Triggers
Anaemia reduces $O_2$ delivery in direct proportion to haemoglobin concentration. Compensatory mechanisms include:
- Increased cardiac output
- Increased tissue oxygen extraction
- Right shift of the dissociation curve (elevated 2,3-DPG)
Patients with poor cardiac reserve (elderly, ischaemic heart disease) cannot compensate via increased cardiac output, and tolerate anaemia less well. The heart, with its baseline $O_2ER$ of 0.6, has minimal reserve for further extraction.
Carbon Monoxide Poisoning
The dual mechanism of COHb (reducing carrying capacity AND left-shifting the remaining curve) means tissue hypoxia is more severe than haemoglobin level alone would suggest. Treatment is high-flow 100% oxygen to competitively displace CO (exploiting the difference in dissociation velocity constants).
Left Shift in Clinical Settings
Hypothermia, alkalosis, and stored blood (which is depleted of 2,3-DPG) all cause left shifts, reducing $O_2$ offloading to tissues. This is relevant in:
- Massive transfusion with stored blood, impaired tissue offloading despite adequate haemoglobin
- Therapeutic hypothermia, reduced metabolic demand partially compensates
- Post-cardiac bypass, hypothermia plus haemodilution compound $O_2$ delivery challenges
Aerobic vs Anaerobic Metabolism
Each glucose molecule yields 38 ATP in aerobic conditions and only 2 ATP anaerobically. Maintaining adequate oxygen delivery to sustain aerobic metabolism is a fundamental goal of anaesthetic management. Histotoxic hypoxia (e.g. cyanide poisoning) prevents cellular utilisation of delivered oxygen by uncoupling oxidative phosphorylation, despite normal $O_2$ delivery.
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