CO is an odorless, clear gas (in extremely high concentrations, it has a lavender odor), with a density of 0.97 that of air. In most instances, CO mixes evenly in turbulent air. A small amount of CO is endogenously produced from the metabolism of hemoglobin to bilirubin and HbCO levels rise in hemolytic anemia. CO may function as an endogenous central nervous system (CNS) neurotransmitter.7

CO forms a ligand with respiratory pigments and enzymes such as hemoglobin, myoglobin, cytochrome P-450, and cytochrome aa3. In fact, cytochrome P-450 was named after the peak (p) absorption of light at 450 pm when the enzyme is 50% saturated with CO. Respiratory enzymes have varying binding affinities for CO compared to oxygen. For example, CO bonds with hemoglobin 210 to 280 times as tenaciously as oxygen, but CO has only one-ninth the affinity of oxygen for cytochrome aa3.8 When CO competes with oxygen for binding sites, it prevents utilization of oxygen by that enzyme or pigment. Thus, HbCO will carry less oxygen according to the number of binding sites occupied by CO.

In addition, the binding of CO to hemoglobin also transforms the oxyhemoglobin dissociation curve from a sigmoid shape to an asymptotic shape, increasing the ability of HbCO to hold on to oxygen at the remaining heme moiety sites (Fig, 19.8.-1). In CO toxicity, both the reduced oxygen carriage and the transformation of oxyhemoglobin dissociation curve impair tissue oxygen delivery. In effect, high HbCO imposes the equivalent of a sudden "chemical" anemia in the patient. The tolerance of the patient to this sudden chemical anemia may be worse than its hemorrhagic equivalent because of the toxic effects of CO on other respiratory pigments and enzymes. While tissue oxygen delivery is decreased, CO delivery still occurs by the dissolved CO in the circulating plasma. Experimental exchange transfusion in dogs of autologous red blood cells (RBCs) exposed extracorporeally to CO before transfusion, resulting in HbCO 60%, demonstrated no signs of CO toxicity. Thus, while impairment of O2 delivery by reduction of O2 carriage is a part of CO toxicity, it may be that delivery of CO contributes more to the toxic effects of CO. In fact, hemoglobin may provide a protective buffer, preferentially binding CO and preventing binding to other respiratory pigments and mitochondrial cytochromes.

decrements in temperature, H+ concentration, CO2 and DPG levels also "shift to the left" of the Hbo2 dissociation curve in a similar fashion.)

CO binding to mitochondrial cytochromes stops electrons—derived from aerobic metabolism of lipids, protein and carbohydrates—from flowing through the cytochrome chain. The cytochrome chain "encases" the fall in energy level of the electrons, allowing a four-electron reduction of nascent O 2 attached to cytochrome aa3 at the end of the mitochondrial cytochrome chain. Thus, oxygen gets reduced to H 2O without formation of potentially destructive oxygen free radical intermediates, such as 0T, OH-, and H2O28 (Fig 198-2). As electrons pass down the cytochrome chain, energy is captured and stored by the generation of ATP in a process called oxidative phosphorylation. CO binding to cytochrome aa3 prevents the attachment of O2, preventing the reduction of O2 to H2O. The cessation of cytochrome oxidative phosphorylation causes CO to "wreck the machine," as Haldane so aptly described the role of CO toxicity in aerobic metabolism.

FIG. 198-2. Nascent oxygen can attach to cytochrome aa3. Oxygen, with its electron-deficient shell, becomes an electron sink (electrophile). Oxygen attached to cytochrome aa3 in this manner prevents the formation of intermediate destructive oxygen free radicals (O', OH , and H2O2). Water is the end product instead.

CO binds strongly to intracellular pigments, such as myoglobin. In muscle with high oxygen utilization, such as the heart, the binding of CO to myoglobin markedly reduces the availability of oxygen for aerobic metabolism. CO poisoning of myocardial myoglobin reduces myocardial contractility, diminishes cardiac output, and further decreases tissue oxygen delivery.

CO toxicity, by imposing ischemic damage, causes white blood cells to become adherent to endothelial surfaces of tissue microvasculature on reperfusion of ischemic tissue.9 Immediately after reperfusion of ischemic CO-poisoned tissue, products from these adherent white cells accelerate cell membrane lipid peroxidation, a process termed reperfusion injury.10

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