Introduction

Oxygen is essential for ATP generation through oxidative phosphorylation, and therefore must be reliably delivered to all metabolically active cells in the body.[1][2] In the setting of hypoxia or low blood oxygen levels, irreversible tissue damage can rapidly occur. Hypoxia can be the result of an impaired oxygen-carrying capacity of the blood (e.g., anemia), impaired unloading of oxygen from hemoglobin in target tissues (e.g., carbon monoxide toxicity), or from a restriction of blood supply. Blood normally becomes saturated with oxygen after passing through the lungs, which have a vast surface area and a thin epithelial layer that allows for the rapid diffusion of gasses between blood and the environment. Oxygenated blood returns to the heart and gets distributed throughout the body via the circulatory system.

The vast majority of oxygen transported in the blood is bound to hemoglobin within red blood cells, while a small amount is carried in blood in the dissolved form. The unloading of oxygen from hemoglobin at target tissues is regulated by a number of factors including oxygen concentration gradient, temperature, pH, and concentration of the compound 2,3-Bisphosphoglycerate. The most important measures of effective oxygen transportation are hemoglobin concentration and the oxygen saturation level, the latter often measured clinically using pulse oximetry. Insults to oxygen-carrying capacity or oxygen delivery must be rapidly corrected to prevent irreversible damage to tissues.

Organ Systems Involved

The lungs are the respiratory organs responsible for the exchange of gasses between the bloodstream and the atmosphere.[3] Venous blood entering the lungs typically has a partial pressure (PO) of 40 mm Hg. Upon passing through the alveolar and pulmonary capillaries, oxygen and carbon dioxide are allowed to equilibrate across the blood-air barrier, resulting in the removal of carbon dioxide from the blood and the absorption of oxygen. Arterial blood leaving the lungs can be expected to have a PO of approximately 100 mg Hg.[4] Oxygenated blood will be carried through the cardiovascular system to peripheral tissues, where oxygen will diffuse down its concentration gradient from high to low concentrations, and be delivered to cells. Here, it will act as the terminal electron acceptor in the process of generating adenosine triphosphate (ATP) through oxidative phosphorylation in the cells.

Many organs possess compensatory mechanisms for hypoxia, but the mechanism most relevant to the discussion of oxygen transport is the production of the hormone erythropoietin (EPO) by peritubular fibroblasts in the renal cortex.[5] Erythropoietin acts to stimulate the proliferation and differentiation of erythrocytes in the red bone marrow--a process known as erythropoiesis. Erythropoiesis results in an increase in the number of erythrocytes (colloquially known as red blood cells), which leads to an increase in total hemoglobin, and ultimately, increased the oxygen-carrying capacity of the blood.

Mechanism

Hemoglobin (Hgb or Hb) is the primary carrier of oxygen in humans. Approximately 98% of total oxygen transported in the blood is bound to hemoglobin, while only 2% is dissolved directly in plasma.[6] Hemoglobin is a metalloprotein with four subunits, each composed of an iron-containing heme group attached to a globin polypeptide chain.[7] One molecule of oxygen can bind to the iron atom of a heme group, giving each hemoglobin the ability to transport four molecules of oxygen.  This ability to sequentially bind oxygen to each subunit results in the unique sigmoidal shape of the oxyhemoglobin dissociation curve. [6] Various defects in the synthesis or structure of erythrocytes, hemoglobin, or the globin polypeptide chain can impair the oxygen-carrying capacity of the blood, and lead to hypoxia.

The body maintains adequate oxygenation of tissues in the setting of decreased PO or increased demand for oxygen. These changes often express as shifts in the oxygen dissociation curve, which represents the percentage of hemoglobin saturated with oxygen at varying levels of PO. Factors that contribute to a right shift in the oxygen dissociation curve and favor the unloading of oxygen correlate with exertion. These include increased body temperature, decreased pH (due to increased production of CO2), and increased 2,3-BPG. (Figure) This right shift of the oxyhemoglobin curve can be viewed as an adaptation for physical exertion. Regulation of the unloading of oxygen from the red blood cells to the target tissues is mostly by the concentration of 2,3-bisphosphoglycerate (2,3-BPG) within erythrocytes. 2,3-BPG preferentially binds to and stabilizes the deoxygenated form of hemoglobin, resulting in a lower affinity of hemoglobin for oxygen at a given oxygen tension, and a subsequent increase in the availability of free oxygen for consumption by metabolically active tissues. 

Another aspect of oxygen transport is the delivery of oxygen to the tissues each minute. This oxygen delivery depends on both cardiac output (CO) and the arterial oxygen content (CaO):

• DO2 = CO * CaO

Note: the CaO calculation is given below. Thus, changes in cardiac output, hemoglobin saturation, and hemoglobin concentration all affect oxygen delivery.

Related Testing

Oxygen is measured in the blood in three ways: partial pressure of dissolved oxygen, the concentration of oxygen, and saturation of hemoglobin. Dissolved oxygen is obtained from arterial blood gas (ABG) measurements, and is reported as partial pressure. Henry’s law dictates that the amount of dissolved oxygen in plasma water is equal to the PO times the solubility constant of oxygen in the blood, which is determined to be 0.003 mL / mmHg O / dL blood. This PO is 40 mmHg in the venous and 100 mmHg in the arterial blood. Oxygen first has to dissolve in blood before it can bind to hemoglobin. The amount of dissolved O2 depends on the oxygen gradient between the alveoli and blood, as well as the ease at which oxygen can move through the alveolar lung tissue itself. (Basically, the parameters involved in Fick’s law of diffusion. [8] 

The most important clinical test in assessing the efficacy of oxygen transportation is the concentration of oxygen (CaO); this is because the vast majority of oxygen in the blood is bound to hemoglobin, while a minimal amount dissolves in plasma water.  Furthermore, the oxygen-carrying capacity of hemoglobin is empirically determined to be 1.34 mL O2 / g Hbg.[9] Thus, when the hemoglobin concentration, hemoglobin saturation (SaO), and PO are known, we can calculate the total oxygen concentration of the blood using the following equation:

• CaO = 1.34 * [Hgb] * (SaO / 100) + 0.003 * PaO2.

The saturation of hemoglobin (SaO2) is another measure of the efficacy of oxygen transport and is the ratio of oxygen bound to hemoglobin divided by the total hemoglobin. This can be determined noninvasively in a clinical setting through the use of pulse oximetry, which measures differences in absorption of specific wavelengths o flight by oxygenated and deoxygenated hemoglobin in the blood. Normal levels should be about 80-100% oxygen saturation of Hb. The limitations of this technique are because it is a ratio tied to total hemoglobin and thus cannot detect anemia or polycythemia. Additionally, pulse oximetry cannot detect anemia or that oxygenated hemoglobin is indistinguishable from hemoglobin that is bound to carbon monoxide. Thus, a person who has suffered exposure to high levels of carbon monoxide may have a normal oxygen saturation as indicated by pulse oximetry, despite lower levels of oxygen bound to hemoglobin.[10]

Pathophysiology

A persistent reduction in oxygen transportation capacity is most often the result of anemia. The definition of anemia is a decrease in the total amount of hemoglobin in the blood (generally less than 13.5 g / dL in males and 12.5 g / dL in females), which results in reduced carrying capacity for oxygen. Anemia can result from disorders leading to the impaired production of hemoglobin (e.g., iron, B12, or folate deficiency), or by the accelerated destruction of hemoglobin, often the result of a defect in hemoglobin structure.

Thalassemias are an important class of inherited disorders resulting in defective production of hemoglobin. An individual with thalassemia has a mutation which impairs production of the globin polypeptide chain of hemoglobin. Thalassemias are classified based upon the number of genes mutated or absent, and whether they encode the alpha globin chain or the beta globin chain. While the presentations and severity of thalassemias vary significantly, they all result in a quantitative defect in hemoglobin production.

Sickle cell anemia ranks as one of the more notable disorders of hemoglobin structure. While the quantity of hemoglobin produced may be normal, a single amino acid substitution of valine for glutamic acid results in a structural defect that promotes the polymerization of deoxygenated hemoglobin. When deoxyhemoglobin polymerizes, it forms fibers that alter the shape of erythrocytes in a process known as sickling.[11] Eventually, repeated stress caused by sickling will damage the membranes of circulating erythrocytes, leading to premature cell death. While sickle cell anemia can remain asymptomatic for a significant time, severe hypoxia may precipitate a sickling crisis, leading to symptoms of generalized pain, fatigue, headache, and jaundice.

Other defects in oxygen transportation may be the result of an environmental toxin, with one example being carbon monoxide poisoning, also known as carboxyhemoglobinemia. The affinity of carbon monoxide for hemoglobin is 210 times that of oxygen.[11] The binding of carbon monoxide to hemoglobin leads to a drastic left shift in the oxygen-hemoglobin dissociation curve, which impairs the unloading ability of oxygen molecules bound to other heme subunits. It is important to note that in the setting of carboxyhemoglobinemia, it is not a reduction in oxygen-carrying capacity that causes pathology, but an impaired delivery of bound oxygen to target tissues.

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