Question

When Charles returned to his apartment at  pm in the evening, he turned on his old kerosene-fueled space heater. It had been a cold day in late spring and his third fl oor apartment was chilly. After spending an hour fi xing dinner, he ate while watching the evening news on tv. He noticed that his vision became progressively blurred. When he got up to go to the kitchen, he felt lightheaded and unsteady. Entering the kitchen, he became very disoriented and passed out. Th e next thing he remembered was waking up in the intensive care unit of the hospital. Some friends who had stopped by about  pm had found Charles unconscious on the kitchen fl oor. Th ey had called an ambulance, which had rushed Charles, still unconscious, to the hospital. An arterial blood sample drawn when he fi rst arrived at the hospital showed the following values:

pN2 = 573 mmHg

pO2 = 93 mmHg
pCO2 = 40 mmHg
pCO = 0.4 mmHg

100 20 80 60 40 60 Po, (mm Hg) 2 Hbco 50% HbCO 80 00 200 15 a 10 O

Describe two physiological mechanisms (or lack of response) that contribute to the lethality of CO poisoning.

Answer 1

Carbon monoxide absorption in plasma is diffusion-limited and binds 200 to 250 times more avidly to hemoglobin than oxygen, effectively displacing oxygen from heme-binding sites. CO decreases oxygen saturation in dose-dependent fashion and shifts the oxygen dissociation curve to the left, despite a normal partial pressure of oxygen (pO₂). A leftward shift of the oxygen dissociation curve causes decreased binding of oxygen to hemoglobin.

In addition to binding to hemoglobin, 10% to 15% of CO binds to other proteins, particularly myoglobin within cardiac muscle.This binding interferes with oxidative phosphorylation, which is necessary for myocardial contraction, and impairs intracellular mitochondrial cytochrome oxidase function. Chest pain, arrhythmias, hypoperfusion, and myocardial injury/ischemia can occur with moderate exposure. The cardiovascular compensatory mechanisms to maintain O₂ concentration in the brain can be overwhelmed by the hypoxemic hypoxia of CO. Nonetheless, the formation of COHgb alone does not account for all the pathophysiologic sequelae.

In dog studies, Goldbaum and colleagues found that neither the transfusion of erythrocytes containing 80% COHgb nor the intraperitoneal injection of CO gas produced CO toxicity, even though the serum COHgb level was above 50%. Dogs inhaling CO died within 2 hours, with an average COHgb level of 65%. This difference in effect is thought to be related to the compensatory cerebrovascular vasodilation and increased cardiac output to maintain O2 delivery to the central nervous system (CNS).In addition to cardiovascular hypoperfusion, CNS toxicity also occurs from synergistic effects of COHgb-mediated hypoxic stress and intracellular oxidative disruption.

Multiple hypotheses explain the mechanism by which CO toxicity leads to cerebral injury. There are acute and delayed neuropathologic changes related to direct CO toxicity (i.e., they are independent of hypoxia-induced injury). Animal models and postmortem human studies suggest the following: (1) Neurotoxicity is secondary to a massive release of excitatory amino acids, particularly glutamate. Glutamate release triggers an ischemic cascade that causes excessive calcium influx, free radical–mediated injury, and inhibition of antioxidant defenses. (2) Carbon monoxide activates neutrophils that produce reactive O2 species and cause brain lipid peroxidation. Peroxidation leads to the degradation of unsaturated fatty acids and the reversible demyelination of CNS lipids. (3) Carbon monoxide increases the production and deposition of peroxynitrite (a potent oxidant) within blood vessel endothelium and brain parenchyma, leading to vascular compromise and cell death in neurons and neuronal cell lines. (4) Reoxygenation injury occurs secondary to the production of partially reduced oxygen species, created during HBO2 treatment. Oxygen species can oxidize essential proteins and nucleic acids, creating injury similar to reperfusion damage.