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Pittman RN. Regulation of tissue Oxygenation. San Rafael (CA): Morgan & Claypool Life Sciences; 2011.


Some general comments about gas exchange and also diffusion will be made, adhered to by a description of how oxygen is brought in the blood. The binding of oxygen come hemoglobin will certainly be discussed, consisting of the oxygen saturation (or dissociation) curve and also factors (allosteric effectors) which cause it to shift. Next, a conversation of the results of carbon monoxide ~ above oxygen binding will be presented. Finally, a description of man-made oxygen carriers will certainly be presented. Most of these topics space covered in traditional textbooks <6,10,54,113> and monographs on oxygen deliver <112>.

Overall Gas Exchange

Table 2 gives the partial pressures of the 4 respiratory gases in dry air, moist tracheal air, alveoli and arterial and venous blood.


The ingredient of alveolar gas relies upon the composition of inspired gas, composition of gas in the practical residual volume (FRC), minus the O2 taken increase by the blood to add the CO2 included from blood. Details of exactly how the listed composition arises are questioned in typical monographs of respiratory tract physiology top top the topic of ventilation/perfusion defects <6,10,54,113>.


Diffusion takes ar in the gas step by the random activity of gas molecules.

Graham"s regulation of diffusion (1833) claims that the price of diffusion the a gas is inversely proportional to the square source of that molecular load (D∼MW−½). Thus, the relative rates of diffusion the CO2 and O2 space equal come √(32/44) or 0.85. Diffusion coefficients in the gas phase room Dgas ≈ 10−1 cm2/sec. In the liquid phase, diffusion rates of gases are usually 10,000 times smaller than those in gas environments as result of the much shorter mean free path between collisions with various other molecules (e.g., the solvent); thus, Dliquid ≈ 10−5 cm2/s <55>. This is no a serious handicap, however, because the ranges over i beg your pardon gas transfer must take ar in the liquid phase are generally quick (about 100 times much shorter than the in the gas phase).

Fick"s law of Diffusion

Fick"s first law says that the amount of gas transferred per unit time (ΔN/Δt) throughout a membrane of thickness Δx is proportional come the area (A) accessible for exchange and the partial pressure distinction (ΔP) that the gas throughout the membrane. The continuous of proportionality (K) is referred to as Krogh"s diffusion coefficient (see below) to identify it native D:


For gas exchange across an alveolus in the lung, A and Δx room the very same for all gases; various transfer rates an outcome from differences in K and also ΔP. For the lung, Δx is about 0.5 μm—a an extremely thin barrier; and also A is around 70 m2—a very large surface area. Krogh"s diffusion coefficient (K = aD) is equal to the diffusion coefficient (D) time the solubility (a) the a gas in the fluid through i beg your pardon the gas diffuses. For example, CO2 is 24 times an ext soluble than O2 in water. Thus, the price of CO2 diffusion is 0.85 × 24 = 20 times as rapid as that for O2 offered the exact same partial push difference.

Summary of Diffusion Properties

Table 3 summarizes the solubilities and also diffusion coefficients for common respiratory gases family member to those components for oxygen (i.e., the values for a offered gas are divided by the worth of that variable for oxygen), wherein α is the solubility (Henry"s regulation coefficient), D is the diffusion coefficient (gas phase), and also K = αD is Krogh"s diffusion coefficient (liquid phase).


Table 3

Solubility, diffusion coefficient, and Krogh"s diffusion coefficient for miscellaneous gases family member to values for oxygen.

Note that all the D values are around the same since the molecule weights of this gases space similar. Thus, differences in diffusion with the liquid phase are identified primarily through the solubility coefficient.

Gas Exchange restricted by Diffusion and Perfusion

A quantitative summary of the gas exchange features of the lungs leads to the conclusion the the exchange of many gases is limited by perfusion (i.e., blood flow). This is the instance for oxygen, so the the blood flowing with the pulmonary capillaries comes into equilibrium with the PO2 in the alveolar gas after traversing about one-third the length of the pulmonary capillaries. One can lug out an evaluation of gas exchange by making use of Fick"s first law to determine the gas transport that take away place between an alveolus and also a little volume the blood as it traverses the gas exchange region of the lung. A similar analysis is carried out because that oxygen in the peripheral circulation in chapter 8. Because that simplicity, gases that just exist in the physically dissolved kind (e.g., He, Ar, N2O) are usually considered, so that one go not have to address the complications added by binding to protein in the blood or carriage in a chemically modified form. This evaluation can be found in countless monographs on respiratory physiology, as well as the much more involved instance of oxygen exchange whereby oxygen binding to hemoglobin within the red blood cells need to be taken right into account <47,113>.

Blood: Plasma and also Red Blood Cells

For purposes of discussing oxygen carry by the blood, us will consider blood come be written of 2 phases: plasma and red blood cell (RBCs). The spring volume that blood populated by RBCs is referred to as the hematocrit, and also its value is a little less 보다 50% in human being adults (∼40% because that females and also ∼45% for males). Oxygen is carried in the blood in two forms: (1) dissolved in plasma and also RBC water (about 2% the the total) and also (2) reversibly bound to hemoglobin (about 98% of the total).

At physiological PO2 (40 < PO2 < 100 mm Hg), only a little amount that oxygen is liquified in plasma due to the fact that oxygen has such a short solubility. In ~ elevated PO2 (breathing 100 % oxygen or throughout hyperbaric oxygenation), however, the physical dissolved kind of oxygen can come to be significant. Henry"s legislation states that the quantity of oxygen liquified in plasma is directly proportional to PO2: = α PO2, where α = 0.003 ml O2 (100 ml plasma)−1 mm Hg−1. Thus, at a PO2 of 100 mm Hg (typical worth for arterial blood), 100 ml that plasma includes 0.3 ml O2 (or 0.3 vol%). Oxygen is lugged in two creates inside RBCs: the is liquified in RBC water (about 70% the RBC volume is water) in accordance through Henry"s law, and also a much larger amount of oxygen is reversibly bound come the hemoglobin had within the RBCs.

Hemoglobin (Heme + Globin)

The protein hemoglobin is a molecule i beg your pardon is responsible for transferring almost every one of the oxygen in the blood. The is written of 4 subunits, each v a heme group plus a globin chain. The heme group is composed of a porphyrin ring which contains an steel (Fe) atom in that is center. Normally, the Fe is in the +2 oxidation state (ferrous) and can reversibly bind oxygen. There room at the very least six gene that regulate globin synthesis in humans, leading to the formation of six structurally various polypeptide chain that are designated α, β, γ, δ, ξ, and also ς chains. All normal and most abnormal hemoglobin molecules space tetramers consist of of two different pairs the polypeptide chains, each chain creating a monomeric subunit.

The blood that a common adult human has at least six different species of hemoglobin molecules, every one of which have the same principal structure and also function. Hemoglobin A (A for adult) renders up 92% of the full hemoglobin concentration in a typical adult human. To date, around 200 structurally different human hemoglobin variants have been reported. This abnormal hemoglobins (relative to hemoglobin A) regularly have different oxygen-binding properties.

Hemoglobin A (HbA) is written of two α chains and two β chains, symbolically composed as α2 β2. Its molecular load is 64,400 Da. Each a chain has actually 141 amino acids, and each β chain has actually 146. The concentration of Hb inside red blood cell is 330 g/l (= 33 g%). In ~ a hematocrit that 45%, this yields a blood that 150 g/1 or 15 g%. The framework of the Hb molecule has been elucidated through the x-ray crystallographic work-related of Perutz and also his co-workers <14,30>. The α and also β chains space arranged in αβ pairs, and also any conformational change in one polypeptide chain is sent to the others in the molecule. There are two various arrangements the the subunits in ~ the tetramer that are much an ext stable 보다 all others. Among these 2 quaternary conformations predominates when the iron atoms are saturated v oxygen (oxy structure), and the other predominates as soon as these binding sites are vacant (deoxy structure). The deoxy structure is defined by the visibility of inter- and intrasubunit salt bridges which offer it a constrained or straff (T) configuration. The oxy conformation is obtained when the salt bonds are damaged so regarding give the tetramer a relaxed (R) quaternary structure.

When the iron atom in the heme group becomes oxidized (loses one electron), the valence state transforms from +2 (ferrous) come +3 (ferric). The hemoglobin is then referred to as methemoglobin (metHb) or ferrihemoglobin (Fe+3 will certainly not bind oxygen). Ordinarily, around 1% of the hemoglobin in a red blood cell is in this form. The level the metHb is kept at this low level generally by the enzyme NADH-methemoglobin reductase. It is important that the level the metHb be retained low since it will not reversibly bind oxygen and thus cannot lug oxygen.

Binding of Oxygen come Hemoglobin: Oxygen Saturation (Dissociation) Curve

The hemoglobin molecule has four binding sites for oxygen molecules: the iron atom in the 4 heme groups. Thus, every Hb tetramer can bind 4 oxygen molecules. Indigenous the molecular weight of Hb, one deserve to calculate the 1 g that Hb can combine with 1.39 ml the oxygen. Actually, several of the Hb generally in red blood cells cannot bind oxygen (it is either metHb or HbCO), and the empirically determined oxygen-binding capacity of hemoglobin (CHb) is 1.34 ml O2 every gram Hb. In 100 ml of blood, over there is about 15 g that Hb, so that 100 ml the blood has actually the capacity to tie 20.1 ml of oxygen. This quantity is called the oxygen-binding volume of blood (CB). Keep in mind that CB is proportional come the hematocrit that the blood.

If one begins with a deoxygenated sample the blood and allows it to equilibrate in actions with gas mixtures of enhancing PO2, the binding sites for oxygen will come to be progressively populated until, in ~ a high enough PO2, all of them will certainly contain oxygen. A curve representing the equilibrium binding the O2 to blood is presented in number 2. The curve is known as the oxygen saturation curve or the oxygen dissociation curve and also expresses the relationship between PO2 and the bound oxygen content.



Oxygen dissociation curve-relating oxygen bound to hemoglobin (oxygen saturation, SO2) together a role of partial press of oxygen (PO2). Native CC Michel, The transfer of oxygen and carbon dioxide by the blood, in respiratory Physiology, eds. AC Guyton, (more...)

P50 is identified as the PO2 in ~ which oxygen saturation is 50%. The standard conditions under i m sorry oxygen binding is measured room T = 37 °C, pH = 7.4 and PCO2 = 40 mm Hg. The fractional oxygen saturation that Hb is the lot of oxygen combined with Hb split by the oxygen-binding volume of the blood (20.1 vol% at normal Hct). The bound oxygen content is proportional to hematocrit:
where is blood hemoglobin concentration and is pertained to hematocrit (Hct) by
where RBC is the typical hemoglobin concentration the a single RBC. That is crucial to recognize the difference between oxygen content and also oxygen saturation:

The oxygen dissociation curve is said to have actually a sigmoid shape, which shows the cooperative nature of oxygen binding to Hb. This curve is extremely nonlinear in the common physiological selection of PO2 (i.e., 40 to 100 mm Hg). The middle section of the curve (20–80% saturation) is steeper than the short PO2 and also high PO2 segments. The affinity the Hb because that oxygen rises steadily as oxygen saturation goes native 0% come 100% because that a given oxygen dissociation curve. For different oxygen dissociation curves, the affinity the Hb for oxygen rises with decreasing P50. A straightforward quantitative summary of the oxygen dissociation is expressed by Hill"s equation <3,30>:
where n is Hill"s coefficient and is about 2.7 for human adult hemoglobin and also is concerned the degree of cooperativity that oxygen binding to hemoglobin. The oxygen-binding characteristic of myoglobin, a associated protein through one heme team that reversibly binds oxygen in striated muscle cells, can additionally be defined by Hill"s equation v n = 1.

Allosteric Effectors of Oxygen Binding come Hemoglobin

Several factors influence the binding that oxygen come hemoglobin: temperature, pH, PCO2 and also 2,3 diphosphoglycerate (2,3 DPG). Increasing the temperature that Hb lowers that affinity for O2 and also shifts the oxygen dissociation curve to the right, as displayed in figure 3. This has actually physiological importance during exercise due to the fact that the temperature the muscle organization is higher than 37°C, and also oxygen have the right to be unloaded indigenous Hb much more easily in ~ the higher temperature (lowered oxygen affinity).


Shifts in the oxygen dissociation curve early out to changes in temperature. From CC Michel, The carry of oxygen and carbon dioxide through the blood, in respiratory tract Physiology, ed. AC Guyton, JG Widdicombe, Baltimore: university Park Press, pp. 67–104, (more...)

As viewed in figure 4, raised H+ task (decreased pH) likewise lowers the affinity that Hb for O2. This was initially noticed through Bohr (Bohr effect) and also his colleagues (1904) as an impact of boosted PCO2, yet it has been presented to be primarily an result of pH inside the red blood cell. CO2 by itself, at consistent pH, likewise affects the oxygen dissociation curve such that increased PCO2 move the curve to the appropriate (i.e., lowers the affinity that Hb for oxygen).


Shifts in the oxygen dissociation curve due to changes in pH. From CC Michel, The transport of oxygen and carbon dioxide by the blood, in respiratory Physiology, eds. AC Guyton, JG Widdicombe, Baltimore: college Park Press, pp. 67–104, 1974. (more...)

2,3 DPG is a glycolytic intermediate developed within the RBC the affects the affinity of Hb because that oxygen. Boosts in RBC reason decreases in <2,3 DPG>, and decreases in RBC cause increases in <2,3 DPG>. 2,3 DPG is a charged ion the cannot permeate the RBC membrane. Boosts in that is concentration change the oxygen dissociation curve to the right. 2,3 DPG is important during respiratory compensation viewed in acclimatization to altitude, through which the hypoxic hyperventilation that high altitude causes PCO2 and H+ come decrease (left shift of oxygen dissociation curve), leading to rise in 2,3 DPG which shifts the curve earlier to the right. 2,3 DPG binding to the terminal amino teams of the beta chains and competes v CO2 because that binding at those sites.

Shifts in the oxygen dissociation curve have the right to be summarized as follows. A right change in the oxygen dissociation curve (↑P50 or ↓ Hb-O2 affinity) can be created by increases in any of the following: T, PCO2, (↓ pH) or <2,3 DPG>. A left shift in the oxygen dissociation curve (↓ P50 or Hb-O2 affinity) deserve to be created by to reduce in any kind of of the following: T, PCO2, ( pH) or <2,3 DPG>. Ordinarily, the Bohr result is not crucial except in exercise. In this situation, the oxygen dissociation curve is change to the right to enable easier unloading the oxygen native Hb in the tissues. The rightward shift in the oxygen dissociation curve is much more important at lower PO2. Back the rightward shift interferes through oxygen loading in the lungs, this never causes a trouble in oxygen transport.

Overall Oxygen Transport

Figure 5 specifies the regular partial pressures and also contents (or concentrations) because that oxygen. It also describes the in its entirety transfer the gas in between the lungs and also blood and between the blood and tissue.


Overall oxygen transport. The partial push of oxygen is shown in the dry air, humidified tracheal wait (PIO2) and also the alveolar compartment (PAO2). ~ pulmonary gas exchange take away place, the composition of arterial blood is displayed (PaO2, a and also (more...)


Carbon monoxide has actually a an extremely high affinity for Hb (200–300 times that of oxygen in typical adults). In situations where there is simultaneously enough oxygen and also carbon monoxide to fully saturate the hemoglobin, these two ligands complete for the very same binding sites, and also the family member amount of each bound to Hb is offered by Haldane"s very first law:
where M lies in the variety 220–270 for normal adult hemoglobin. Because that example, if PCO = 0.08 mm Hg and PO2 = 80 mm Hg, about 20% that the Hb is bound up through CO (if M = 250). This to represent 20% that the Hb that cannot carry oxygen (i.e., there is one component of HbCO to four parts the HbO2). Figure 6 illustrates the result of CO ~ above the oxygen dissociation curve.


Effect the carbon monoxide on the oxygen dissociation curve. From CC Michel, The transport of oxygen and also carbon dioxide through the blood, in respiratory Physiology, eds. AC Guyton, JG Widdicombe, Baltimore: university Park Press, pp. 67–104, 1974. (more...)

The curve labeled “50% Anaemia” to represent a sample of blood whose oxygen-binding capacity is one-half the typical value, and none of the hemoglobin is an unified with CO. Compare this curve v the one labeling “50% HbCO” just over it (HbCO = 50%) that likewise has one oxygen-binding volume of one-half the typical value and note the the blood with HbCO has actually a left-shifted oxygen dissociation curve.

Carbon monoxide is dangerous for number of reasons. Once CO binds to one of the binding sites on hemoglobin, the boosted affinity that the various other binding sites because that oxygen leads to a left shift of the oxygen dissociation curve and interferes with unloading that oxygen in the tissues. The presence of CO stays clear of loading the oxygen because of competition because that the very same binding sites. Carbon monoxide binding tightly to hemoglobin (high affinity because that hemoglobin), and the cumulative effect of its binding approximately the border given above by Haldane"s very first law mirrors that really low partial pressure of CO (<1 mm Hg) can efficiently block a large portion of the heme-binding sites native oxygen. Thus, the oxygen content of blood in the existence of carbon monoxide is much lower than normal. Blood remains red since the absorb spectrum for HbCO is similar to that of HbO2, except that that is change slightly to higher wavelengths compared with HbO2. Finally, there space no apparent physical signs of carbon monoxide poisoning since carbon monoxide is colorless, odorless and also tasteless; it does not produce respiratory reflexes prefer coughing or sneezing; there is no rise in ventilation (thus, PaO2 is normal); and no feeling of difficulty in breathing.


In situations where there is a far-ranging (∼30–40%) ns of blood volume (i.e., hemorrhage, watch Chapter 9), the is essential to reclaim blood volume as soon as possible, so the the capacity of the blood to bring oxygen come the tissues is not seriously compromised. The natural fluid for together transfusions is whole blood due to the fact that it has all the biologically relevant materials normally present in blood. Because of concerns around the extent and also safety of the blood supply, consisting of adverse transfusion reactions and also inadvertent transmission of contagious diseases, there has actually been a great effort to produce man-made oxygen carriers that deserve to act as substitutes for whole blood transfusions. Two varieties of fluids have actually been occurred for this purpose, hemoglobin-based oxygen carriers and also perfluorocarbon emulsions. Their qualities in regard come oxygen transport and also regulation of tissue oxygenation will currently be presented.

Hemoglobin-Based Oxygen Carriers

Since plasma cannot bring much oxygen, because of its short solubility because that oxygen, and also hemoglobin is the oxygen carrier within RBCs, it is natural to think about hemoglobin once formulating an fabricated oxygen carrier. Number of hemoglobin-based oxygen carriers (HBOCs) room in various stages of breakthrough for the objective of treating hemorrhagic and hypovolemic shock in trauma patients and also other scenarios where there is a endangered oxygen supply <9,12,116,117>. HBOCs space made from expired human being blood or fresh bovine blood which undergoes numerous adjustments to make them safe and effective oxygen carrier <12>. The RBCs are first lysed to release their hemoglobin, and then the stroma is eliminated by a variety of methods, consisting of centrifugation, filtration and chemical extraction <50>. The stroma-free hemoglobin is climate purified and undergoes modifications to cross-link, polymerize or conjugate it to various other compounds. Without these modifications, the oxygen affinity that the stroma-free hemoglobin is too great to facilitate oxygen relax in the tissues as result of the reduction in 2,3 DPG. Once it is outside the RBC, hemoglobin swiftly dissociates into 32 kDa αβ dimers and also 16 kDa α or β monomers, both of i m sorry are promptly filtered in the kidney and can precipitate in the loop the Henle, resulting in severe renal toxicity <36>. Because that this reason, four different species of HBOCs have been considered: cross-linked hemoglobins, cross-linked and polymerized hemoglobins, hemoglobins conjugated to macromolecules and encapsulated hemoglobins <12>.

The many notable impact following management of HBOCs is a pressor effect, boost of mean arterial blood push (MAP) by as much as 10–35% within 15–30 minutes following management <36>. The push usually return to baseline in ~ 2 hours following administration in most animal studies. The dimension of the HBOC shows up to beat a function in this pressor effect. Smaller sized HBOCs, such together cross-linked tetramers, create a bigger rise in MAP 보다 do bigger polymerized versions, possibly due to extravasation that smaller materials of HBOCs indigenous the microcirculation. Over there are number of theories regarding why the pressor impact occurs <9,50,89>, however the most favored possibility has something to perform with the interaction of hemoglobin with nitric oxide (NO). Nitric oxide exit from endothelial cells relaxes the smooth muscle in the blood ship walls. Normally, that is assumed that the RBC membrane prevents NO from interacting with hemoglobin. However, the cell-free hemoglobin the HBOCs reacts freely with NO to develop HbNO indigenous deoxyhemoglobin and methemoglobin and nitrate native oxyhemoglobin, causing a reduction in NO and also leading to an unopposed vasoconstriction <50>. One more mechanism that has been proposed come account for the arteriolar vasoconstriction and elevated MAP considers the the HBOC rises the oxygen-carrying volume of blood and produces an oversupply that oxygen to the tissues, causing a compensatory autoregulatory vasoconstriction <89,116,117>. However, a pressor effect has been observed in instances where little amounts of HBOC have actually been infused, too small to have an effect on oxygen supply.

In the existence of one HBOC, the full oxygen concentration the blood is given by:
where D is the dissolved oxygen provided by αO2 PO2, RBC is SO2RBC Hct RBC CHb and HBOC is SO2HBOC (1-Hct) HBOC CHb. RBC is the average concentration that hemoglobin in one RBC, and HBOC is the concentration the HBOC in the plasma. The presumption is made the the oxygen-binding volume of hemoglobin is the very same for the hemoglobin in the RBC and also that consisting of the HBOC. This assumption can be relaxed if the oxygen-binding capacities are known to be different. Since the oxygen dissociation curves for RBC hemoglobin and also the HBOC will usually be various (i.e., different P50s and Hill coefficients, view Eq. 4.5), one would expect the SO2 worths to be different, even assuming the equilibrium exists for PO2 between the RBCs and the HBOC.

Perfluorocarbon Emulsions

Perfluorocarbon-based emulsions (PFCs) are mixtures the fluorocarbons and also emulsifying agents the differ considerably in structure and mechanism of activity from HBOCs. Fluorocarbons differ in shape and also size, however share many of the same general chemical characteristics. This molecules room hydrocarbon chains that are extremely substituted with fluorine atoms. The carbon-fluorine bonds offer them their unique chemical and also biological inertness. Fluorocarbon molecules supplied in potential synthetic oxygen carriers deserve to be straight or cyclic, back it has been shown that straight molecules dissolve greater quantities of oxygen <85,89>. Fluorocarbons have a high gas-dissolving capacity and also low viscosity but are very insoluble in aqueous solutions; they should be emulsified in order to travel through the circulatory system. Surfactants, or surface-active agents, are supplied as emulsifiers to form small droplets that space 0.1 come 0.3 μm in diameter. Lock are capable of dissolving big quantities that gases, such as oxygen and carbon dioxide; however, they lug less oxygen 보다 hemoglobin chin <68,95>. Castle are qualified of delivering oxygen to the organization passively and also can lug an lot of oxygen proportional come the approximately PO2 without having to count on the red blood cells <68>.

PFCs have actually a half-life clearance native the human body of roughly 2–4 hours and also are got rid of unmetabolized through the lung after being taken up by the reticuloendothelial device (RES) <89>. This quick half-life can potentially border clinical supplies in traumatic injury and hemorrhagic shock. The most crucial limitation that PFCs is the direct relationship in between dissolved oxygen concentration and also PO2. Several side effects have been reported because that PFCs <89,96>, and little is known about the long-term impacts of PFC retention.

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Unlike hemoglobin molecules, PFCs execute not bind oxygen, so the oxygen is carried by PFCs only in the liquified form. Thus, the concentration of oxygen brought by PFCs is offered by Henry"s legislation <85,97>:
where αPFC is the solubility of oxygen in the PFC emulsion. The relationship between oxygen concentration and also PO2 for hemoglobin is sigmoidal in shape, whereas it is straight for PFCs. In contrast to the oxygen bound to hemoglobin, oxygen dissolved in PFCs is not affected by pH, 2,3 DPG or various other physicochemical factors <97>.