Why does the oxygen dissociation curve shift to the left in carbon monoxide (CO) poisoning?

Why the Oxygen Dissociation Curve Shifts Left in Carbon Monoxide Poisoning

Carbon monoxide shifts the oxyhemoglobin dissociation curve to the left because CO binding to hemoglobin increases the oxygen affinity of the remaining unoccupied heme sites, making hemoglobin hold onto oxygen more tightly and preventing oxygen release to tissues. 1

The Dual Mechanism of Tissue Hypoxia

CO poisoning causes tissue hypoxia through two distinct hemoglobin-related mechanisms that work synergistically:

Primary Mechanism: Reduced Oxygen-Carrying Capacity

• CO binds to hemoglobin with an affinity approximately 220 times greater than oxygen, forming carboxyhemoglobin (COHb) and directly reducing the number of sites available for oxygen transport 1, 2
• This competitive binding displaces oxygen from hemoglobin molecules, creating a form of "anemic hypoxia" where total oxygen content in blood is severely reduced 3

Secondary Mechanism: Left Shift of the Dissociation Curve

• When CO occupies some heme sites on the hemoglobin molecule, it alters the conformational structure of the entire hemoglobin tetramer, increasing the oxygen affinity of the remaining unbound heme sites 1
• This left shift means that even the oxygen that IS bound to hemoglobin is held more tightly and released less readily to tissues, further reducing tissue PaO2 1, 3
• The combination of reduced oxygen-carrying capacity PLUS impaired oxygen release creates a "double hit" that severely compromises tissue oxygenation 1

Clinical Implications of the Left Shift

Why Standard Monitoring Fails

• PaO2 typically remains normal in CO poisoning because it measures only dissolved oxygen in plasma, which is unaffected by CO binding to hemoglobin 3
• Standard two-wavelength pulse oximeters cannot differentiate carboxyhemoglobin from oxyhemoglobin, showing falsely reassuring SpO2 readings >90% even when COHb levels reach 25% 1, 3
• Older blood gas analyzers without CO-oximetry calculate SaO2 based only on PaO2 and pH, reporting falsely normal oxygen saturation (97-98%) despite high COHb levels 1

The Severity Paradox

• Clinical severity does not correlate with COHb levels, as patients may have significant toxicity despite relatively low COHb percentages 3
• This occurs because the left shift effect on oxygen delivery, combined with direct cellular toxicity mechanisms, causes tissue damage independent of the absolute COHb level 1

Beyond Hemoglobin: Additional Toxic Mechanisms

While the left shift explains impaired oxygen delivery, CO poisoning involves multiple other pathophysiologic mechanisms that contribute to morbidity and mortality:

• CO binds to intracellular heme proteins including myoglobin (worsening cardiac hypoxia) and cytochrome oxidase (impairing mitochondrial ATP production) 1, 2
• Nitric oxide generation leads to peroxynitrite production and lipid peroxidation 1, 3
• Mitochondrial oxidative stress, apoptosis, and immune-mediated injury occur even after COHb levels normalize 1, 2

Critical Diagnostic Pitfall to Avoid

Never rely on pulse oximetry or calculated oxygen saturation to rule out CO poisoning. The left-shifted curve combined with normal PaO2 creates a dangerous clinical scenario where patients appear well-oxygenated by standard monitoring but are actually experiencing severe tissue hypoxia 1, 3. Always obtain direct carboxyhemoglobin measurement via laboratory CO-oximetry (spectrophotometry) when CO poisoning is suspected 1.