Oxygen and Carbon Dioxide Transport in Blood Robert M. Lust Brody School of Medicine East Carolina University, Greenville, USA ã 2007 Elsevier Inc. All rights reserved.
Gas exchange occurs by diffusion at both the tissue and alveolar capillaries, with the direction of movement of gases determined by the relative concentration gradients (the difference in partial pressures) for each across the membrane. The rate at which diffusion occurs is determined by the magnitude of the concentration gradient, the solubility of the gas through the membrane unit, the surface available at the capillary/alveolar membrane, and the thickness of the membrane unit. Once the gases have been exchanged at the respective membrane units, they must be transported through the circulatory system to the next exchange location, such as from pulmonary capillaries to tissue capillaries, or from tissue capillaries to pulmonary capillaries. Described below is the manner in which gases are transported in blood (for reviews, see Maizes et al (2000), Geers and Gros (2000) and Elad (1999)). OXYGEN TRANSPORT. As oxygen has poor solubility in plasma, with only about 0.00003 ml dissolved oxygen/ml blood/mm Hg oxygen partial pressure, >99% of total blood oxygen is transported in the blood by hemoglobin, a carrier protein. Hemoglobin, which is composed of two alpha polypeptide chains, two beta polypeptide chains, and four heme groups, is located within the erythrocyte or red blood cell (RBC). Heme is a flat, iron-containing, protoporphyrin disk that binds one molecule of oxygen (Fig 1). Therefore, normal hemoglobin is capable of carrying four oxygen molecules. As an individual erythrocyte may contain as many as 300 molecules of hemoglobin, each erythrocyte is capable of transporting well over 1000 molecules of oxygen. The production of RBCs is under the control of erythropoietin, which is released by the kidneys in response to oxygen tensions (for reviews, see Schmidt (2002), Spivak (2001), or Maizes et al (2000)). To properly bind oxygen, the iron in hemoglobin must be in the ferrous state (Fe++). If the iron is in the ferric state (Fe+++), the oxygen-binding capacity of the hemoglobin is greatly reduced and the hemoglobin is referred to as methemoglobin. Drugs such as nitrates and sulfonamides increase the relative amount of methemoglobin, and thereby decrease the oxygen-carrying capacity of the RB C. Some genetic hemoglobin defects,
Fig. 1. Diagrammatic representation of hemoglobin structure.
Oxygen and Carbon Dioxide Transport in Blood
such as Thalassemia (alpha or beta) and sickle cell anemia, are associated with altered hemoglobin structure and function, and decreased oxygen transport capacity. Similarly, diabetes can lead to glycosylation of the beta subunit resulting in a decreased total oxygen-binding capacity by the RBC. The specific relationship between hemoglobin and oxygen is characterized graphically by the oxyhemoglobin saturation curve (Fig 2). As hemoglobin functions as a binding protein for oxygen, hemoglobin saturation varies as a function of substrate concentration, given as the partial pressure of oxygen. The normal oxyhemoglobin saturation curve (blue line in Fig 2) is not linear, but rather sigmoidal in shape. This indicates that hemoglobin is more than 90% saturated even when the arterial PO2 falls as low as 70 mm Hg. This characteristic of hemoglobin binding provides a margin of safety to the organism, enabling a relatively high and constant degree of blood oxygenation to be maintained despite wide variations in oxygen partial pressure, as might occur with exposures to different ambient gas pressures as occurs with changes in altitude. At normal values for arterial PO2 (PaO2 in Fig 2), hemoglobin is more than 98% saturated with oxygen. Likewise, there is a physiological advantage to the affinity characteristics of hemoglobin at partial pressures of oxygen below 55-60 mm Hg. In this range of oxygen, pressures the hemoglobin-binding curve steepens. The significance of the transition is that, in this range of oxygen pressures, small changes in PaO2 produce relatively large changes in hemoglobin saturation. Thus, even small changes in oxygen use at the tissue level, which produces a slight decrease in partial pressure, will greatly enhance oxygen "unloading" by hemoglobin, resulting in improved oxygen delivery to the tissue. However, despite the increased unloading as the PaO2 decreases, hemoglobin in a normal venous blood sample is still more than 70% saturated (PvO2 in Fig 2). While the affinity of hemoglobin for oxygen dictates the oxyhemoglobin saturation, the affinity is not fixed. As the binding curve is nonlinear, changes in affinity cannot be represented simply as a change in the slope of the relationship. Instead, a value known as the P50, which describes the partial pressure of oxygen at which the hemoglobin is 50% saturated, is used to indicate affinity. The affinity can be altered by changes in the partial pressure of carbon dioxide, the pH, the temperature, and the concentration of 2,3-diphosphoglycerate (2,3-DPG) in the blood, the latter produced by RBCs during glycolysis.
Fig. 2. Summary of oxyhemoglobin dissociation characteristics.
Oxygen and Carbon Dioxide Transport in Blood
Increased hemoglobin affinity (red line in Fig 2) is characterized as a leftward shift in the saturation curve or a decrease in the P50. This can be caused by decreased pCO2, decreased temperature, decreased 2,3-DPG, or increased pH (decreased [H+]). The functional significance of increased affinity is that the hemoglobin remains saturated longer. The blood changes that occur with increased affinity, which are consistent with decreased metabolic demand, promote oxygen binding. The shift towards increased hemoglobin affinity for oxygen that is caused by decreasing carbon dioxide concentration is referred to as the Haldane effect. Similarly, under conditions consistent with increased metabolic demand, such as increased carbon dioxide production, decreased pH, increased temperature, or increased 2,3DPG, the affinity of hemoglobin decreases (the P50 increases). Physiologically, the functional significance of the rightward shift in affinity (purple line in Fig 2) promotes oxygen delivery or "hemoglobin unloading". The shift towards decreased hemoglobin affinity that is caused by an increased carbon dioxide concentration is referred to as the Bohr effect. As a major factor influencing the diffusion of oxygen into the blood is the partial pressure of the gas, a useful term in describing oxygenation of the blood is the partial pressure of oxygen in arterial blood, or the PaO2. However, because arterial partial pressure only represents the fraction of oxygen dissolved in plasma, which is low, PaO2 is a good indicator of the adequacy of diffusional gas exchange at the pulmonary capillary, but not a good indicator of the total oxygenation of arterial blood. Typically, blood leaving the pulmonary capillaries is saturated with oxygen, while blood returning to the pulmonary capillaries generally is referred to as desiderated. Therefore, percent saturation is a term used in describing the oxygen characteristic of blood. In general, because oxygen and hemoglobin are linked as substrate and carrier, as the partial pressure of oxygen in plasma changes the relative saturation of hemoglobin should also change. Although percent saturation describes the extent to which hemoglobin is saturated with oxygen, it is not a good indicator of overall blood oxygen content. Thus, a small amount of hemoglobin, in the setting of an adequate PaO2, will still produce a high-saturation value despite limited total oxygenation, as occurs with anemia. However, in chronic monitoring conditions, where the amount of hemoglobin is not expected to change, monitoring the saturation of hemoglobin is a viable alternative to repeatedly sampling arterial blood to obtain partial pressures. Oxygen saturation can be monitored noninvasively by pulse oximetry. This is useful for tracking the adequacy of ventilation when the availability of direct arterial blood-gas sampling is limited and no changes in hemoglobin are expected over the course of time that pulse oximetry is utilized. Pulse oximetry machines are single wavelength spectrophotometers tuned to the characteristic absorbance of oxygenated hemoglobin. Pulse oximetry takes advantage of the fact that hemoglobin bound with oxygen absorbs light at a characteristic frequency that corresponds visually to a bright red, so that as hemoglobin is desaturated of its oxygen, as seen in venous blood, the relative intensity of the light signal decreases at that frequency. Two other terms that describe the oxygenation characteristics of the blood are oxygen-carrying capacity and oxygen content. Oxygen-carrying capacity (O2 capacity, or simply capacity) describes the amount of oxygen the blood could carry if gas exchange was unimpaired and the hemoglobin is fully saturated. Blood-oxygen content (O2 content, or simply content) describes the total amount of oxygen actually contained by any given blood sample. The actual amount of hemoglobin and the partial pressure of oxygen in the blood must be known to determine the blood-oxygen content. The percent saturation of hemoglobin can be determined from the partial pressure of oxygen (see Fig 2), with the amount of oxygen dissolved in the plasma determined and defined by: Total O2 Content = (Hb/unit blood)(O2 binding capacity/unit Hb)(% Hb saturation) + (PB-PH20)(Fi02)(0.003 mlO2/100 ml blood)
Oxygen and Carbon Dioxide Transport in Blood
where Hb = hemoglobin (typically 14.7 g/100 ml/blood), PB = barometric pressure (at sea level 760 mm Hg), PH20 = partial pressure of water vapor (47 mm Hg) at body temperature (37 C), and Fi02 = fraction of oxygen in inspired air (typically 0.209). The normal binding capacity is 1.34-1.37 ml O2 /g Hb, so that the total oxygen content in a typical, normal arterial-blood sample, 99% saturated with oxygen, is (14.7g Hb/100 ml blood)(1.34 ml O2 /g Hb)(0.99) +(760-47)(0.209)(0.003 mlO2/100 ml blood), = 19.5 + 0.45 ﬃ 20 ml O2/100 ml blood; or 20 ml O2/100 ml blood, or 20 vol%, or 200 ml O2 /liter blood. CARBONDIOXIDETRANSPORT. As carbon dioxide is more soluble in plasma than oxygen, more (11%) of the total CO2 is carried as dissolved gas. However, the majority (64%) of total blood carbon dioxide is carried in an ionic form as bicarbonate ion (HCO-3) (see Fig 3).
Fig. 3. Summary of carbon dioxide transport and exchange at the tissue capillary.
As blood passes through tissue capillaries, oxygen moves along it’s concentration gradient from RBCs to tissues, and carbon dioxide diffuses along its concentration gradient from the tissues to the blood. A significant amount of the CO2 diffuses from the blood into the RBC where, in a reaction catalyzed by carbonic anhydrase, it combines with water to form carbonic acid (H2CO3). The same reaction occurs in plasma, but at a much slower rate Geers and Gros (2000), Elad (1999). The carbonic acid immediately dissociates into hydrogen (H+) and bicarbonate ions (HCO-3), with the bicarbonate ion formed in the RBC diffusing into the plasma. To preserve electrical balance across the erythrocyte membrane, the bicarbonate transfer out of the RBC is matched by an influx of chloride ions that causes a slight osmotic pressure that draws water into the RBC as it passes along the tissue capillary. The influx of carbon dioxide into the erythrocyte, and the hydrogen ion that results, slightly acidifies the RBC cytoplasm and binds to the hemoglobin, leading to a decrease in the affinity of the hemoglobin for oxygen. Thus, the increase in CO2 that occurs with transit of the RBC through a tissue capillary enhances oxygen unloading to the tissue. This process is essentially reversed at the pulmonary capillary (Fig 4). In this case, oxygen moves along its concentration gradient from the alveolar space to the blood, and
Oxygen and Carbon Dioxide Transport in Blood
CO2 travels along its concentration gradient from the pulmonary capillary to the alveolar space. Hydrogen ion is released in the cell as the concentration of oxygen increases within the RB C. As CO2 leaves the cell along its gradient, and H+ is liberated by increased oxygen binding, the carbonic anhydrase catalyzed reaction is driven in the opposite direction. When this occurs, bicarbonate ion diffuses back into the RBC where it is recombined with hydrogen ion to form carbonic acid, which then dissociates to water and CO2. The carbon dioxide diffuses out of the cell and into the alveolar space. The influx of bicarbonate ion is balanced by an efflux of chloride ion back to the plasma, and is accompanied by a slight loss of intracellular water, reversing the osmotic flux that occurs at the tissue capillary. As the erythrocyte releases carbon dioxide, the pH within the RBC increases, enhancing the affinity of hemoglobin for oxygen. Thus, as blood passes along the pulmonary capillary gaining oxygen and giving up carbon dioxide, it becomes more efficient, and "oxygen loading" is enhanced. In fact, both the Bohr effect (at the tissue capillary) and the Haldane effect (at the pulmonary capillary) can be seen in a single pass of blood through the circulation. These effects are important mechanisms for enhancing the efficiency of gas transfer at both exchange sites.
Fig. 4. Summary of carbon dioxide exchange and transport at the pulmonary capillary.
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Journal Citations Maizes, J.S., Murtuza, M., Kvetan, V., 2000. Oxygen transport and utilization. Respir. Care Clin. N. Am., 6 (4), 473–500. Schmidt, W., 2002. Effects if intermittent exposure to high altitude on blood volume and erythropoeitic activity. High Alt. Med. Biol., 3(2), 167–176.
Oxygen and Carbon Dioxide Transport in Blood Spivak, J.L., 2001. Erythropoietin use and abuse: When physiology and pharmacology collide. Adv. Exp. Med. Biol., 502, 207–224. Geers, C., Gros, G., 2000. Carbon dioxide transport and carbonic anhydrase in blood and muscle. Physiol. Rev., 80(2), 681–715. Elad, D., 1999. Biotransport in the human respiratory system. Technol. Health Care, 7(4), 271–284.