Absorption

Carbon monoxide is absorbed rapidly through the lungs at the level of the alveolus.¹ The quantity of gas absorbed is dependent on minute ventilation (the product of respiratory rate and tidal volume), duration of exposure, and the concentration of carbon monoxide in the environment.¹ Once absorbed into the blood and circulated throughout the body, a small amount of carbon monoxide is oxidized to carbon dioxide, some remains as gas in solution, and some binds to heme proteins including hemoglobin, myoglobin, and cytochrome a₃ in mitochondria.^1,4 Studies indicate that the binding of carbon monoxide to heme proteins and its presence in plasma result in different aspects of its toxicity. The pathophysiology of carbon monoxide toxicity involves two main mechanisms: impaired oxygen delivery to tissues (hypoxia) and direct cellular toxicity.^1,2,4,7,10

Hypoxic Toxicity

The hypoxic mechanism of carbon monoxide toxicity involves the interaction of carbon monoxide with hemoglobin in the blood: carbon monoxide displaces oxygen from hemoglobin and causes an allosteric hindrance of oxygen release from hemoglobin to the tissues.^4,16 The resultant tissue hypoxia results in cellular shock, CNS depression, and cardiovascular compromise.

Carbon monoxide competes with oxygen for hemoglobin binding sites with 200 to 250 times the affinity.^1,16 Carbon monoxide binds two of the four available heme groups in each molecule of hemoglobin, causing a decrease in the oxygen carrying capacity of 50% (Figure 87-1) and shifting the oxyhemoglobin dissociation curve down.^16,17 Thus very low levels of carbon monoxide in the blood result in markedly reduced oxygen carrying capacity despite a normal hemoglobin concentration and normal partial pressure of oxygen.

Figure 87-1 A comparison of oxygen content of the blood based on the partial pressure of oxygen in various scenarios: normal, anemia with a 50% reduction in hemoglobin (50% [Hb]), and a carboxyhemoglobin level of 50% (50% HbCO). Both anemia and carboxyhemoglobin result in a significant decrease in the oxygen-carrying capacity of the blood.

From Berne RM, Levy MN, Koeppen BM, Stanton BA, editors: Physiology, ed 5, St Louis, 2005, Mosby.

The dissociation of oxygen from hemoglobin is also affected by carbon monoxide, which binds tightly to hemoglobin, markedly disturbing the chemical equilibrium of the molecule.^16,17 The change in equilibrium of the COHb results in an interference with both the association and dissociation of oxygen.¹⁶ Therefore oxygen bound to hemoglobin, which is also bound to carbon monoxide is not easily released to the tissues, and the oxyhemoglobin dissociation curve is shifted to the left (Figure 87-2).^16,17 Decreased release of oxygen to the tissues exacerbates the cellular hypoxia caused by decreased oxygen content and subsequent delivery.

Figure 87-2 Oxygen saturation curves of hemoglobin, carboxyhemoglobin, and myoglobin. Note the leftward shift of the carboxyhemoglobin curve denoting a decreased release of oxygen to the tissues.

From Berne RM et al, editors: Physiology, ed 5, St Louis, 2005, Mosby.

Cellular Toxicity

Hypoxia alone, however, does not explain the variation in individual response to a given level of COHb and the delayed neurologic syndrome associated with carbon monoxide toxicity. Studies have demonstrated cerebral hyperemia, tachycardia, and tachypnea during carbon monoxide toxicity, representing a compensatory mechanism to maintain oxygenation in the face of decreased oxygen carrying capacity.^1,7,18 Therefore the brain does not commonly suffer from hypoxia during carbon monoxide toxicity unless there is accompanying cardiovascular dysfunction or severely elevated levels of COHb (>70%), overwhelming the adaptive response.^7,18 A study was performed comparing the clinical signs of dogs subjected to inhaled carbon monoxide with dogs bled to a hematocrit of approximately 25% and subsequent volume replacement with crystalloid and colloid fluids or COHb-containing red blood cells.¹⁹ The dogs subjected to inhaled carbon monoxide achieved COHb levels of 54% to 90% and died. The dogs bled to an anemic state and given COHb-containing red blood cells to achieve a COHb level of 60% survived indefinitely with an outcome similar to that of dogs who were bled and received volume replacement with crystalloid and colloid solutions.¹⁹ This study confirmed the suspicion that a mechanism other than hypoxia from high levels of COHb results in toxicity. This mechanism is thought to be the consequence of cellular toxicity.^2,4,7,19 Cellular toxicity associated with carbon monoxide poisoning appears to involve both direct and indirect mechanisms.

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