The Bohr and Haldane Effects in the Oxyhemoglobin Dissociation Curve
The Bohr Effect: Hydrogen Ions Facilitate Oxygen Unloading
The Bohr effect is the mechanism by which increased hydrogen ions (H+) and CO₂ in metabolically active tissues cause hemoglobin to release oxygen more readily by shifting the oxyhemoglobin dissociation curve to the right. 1
Mechanism and Physiological Basis
H+ ions bind to specific amino acid residues (Bohr groups) on hemoglobin, causing allosteric conformational changes that decrease hemoglobin's affinity for oxygen 1
In metabolically active tissues, increased CO₂ production leads to formation of carbonic acid (H₂CO₃), which dissociates into bicarbonate (HCO₃⁻) and H+ ions via the reaction: CO₂ + H₂O → H₂CO₃ → H⁺ + HCO₃⁻ 1
The resulting increase in H+ concentration (lower pH/acidosis) triggers the Bohr effect, enhancing oxygen release precisely where oxygen demand is highest 1
The magnitude of the Bohr effect profoundly influences both the shape and position of the oxygen equilibrium curve—blocking the Bohr effect dramatically increases oxygen affinity and shifts P50 from 6 to 46 mmHg when varying Bohr groups from 0 to 8 per hemoglobin tetramer 2
Clinical Significance in Disease States
The Bohr effect is more important for oxygen delivery than previously recognized—it has a more profound effect on gas exchange than the Haldane effect's contribution to CO₂ transport 3, 2
In COPD patients with acute respiratory failure, mechanical ventilation swiftly corrects severe respiratory acidosis, causing intracellular alkalotic pH through the Bohr effect, which paradoxically shifts the curve left and can impair oxygen delivery despite improved oxygenation 4
Arterial blood shifts right by approximately 4 mmHg at pH 7.24 and left by -3.5 mmHg at pH 7.51, with venous blood showing even greater shifts (4.8 mmHg right at pH 7.24 and -4 mmHg left at pH 7.51) 5
The actual Bohr coefficient in mammals (-0.35 to -0.5) maximizes the rightward shift of the oxygen equilibrium curve in tissues and is therefore optimal for oxygen delivery rather than for pH homeostasis 6
The Haldane Effect: Deoxygenation Enhances CO₂ Binding
The Haldane effect describes how deoxygenated hemoglobin has increased capacity to bind CO₂ and H+ ions, facilitating CO₂ removal from tissues and transport to the lungs. 7
Mechanism and Clinical Impact
When oxygen is released from hemoglobin in peripheral tissues, the deoxygenated hemoglobin becomes a better buffer for H+ ions and can bind more CO₂, enhancing CO₂ removal from metabolically active tissues 7
Conversely, when hemoglobin binds oxygen in the lungs, it releases H+ ions and CO₂, facilitating CO₂ elimination through ventilation 7
Increasing FiO₂ decreases the carbon dioxide buffering capacity of hemoglobin through the Haldane effect, which can contribute to CO₂ retention in patients with limited ventilatory reserve 7
Critical Clinical Applications in Respiratory Disease
Oxygen Therapy in COPD and Hypercapnic Patients
When high-concentration oxygen is administered to COPD patients, the Haldane effect contributes to hypercapnia by reducing hemoglobin's CO₂ buffering capacity, though V/Q mismatch from reversal of hypoxic pulmonary vasoconstriction is the more important mechanism 7
Target oxygen saturation of 88-92% in COPD patients reduces mortality compared to high-concentration oxygen, as excessive oxygen can worsen hypercapnia through multiple mechanisms including the Haldane effect 8
The goal of oxygen therapy is to maintain PaO₂ ≥8 kPa (60 mmHg) or SpO₂ ≥90%, which corresponds to the flat portion of the oxyhemoglobin dissociation curve where small decreases in PaO₂ do not produce large reductions in saturation 7
Understanding Curve Shifts in Clinical Practice
Left shift (increased oxygen affinity):
- Caused by decreased H+ (alkalosis/increased pH), decreased temperature (hypothermia), decreased 2,3-DPG, and methemoglobinemia 9, 8
- Results in "functional anemia" where tissues experience hypoxia despite normal hemoglobin levels and SpO₂ readings because oxygen binds too tightly and is not released adequately 9, 8
- Normal SpO₂ readings can mask significant tissue hypoxia in patients with left-shifted curves—always confirm with arterial blood gas and co-oximetry when suspecting methemoglobinemia or CO poisoning 9, 8
Right shift (decreased oxygen affinity):
- Caused by increased H+ (acidosis/decreased pH), increased CO₂, increased 2,3-DPG, and increased temperature 8, 1
- Facilitates oxygen release to tissues where it is most needed 8
- Often represents appropriate physiological compensation in chronic anemia or chronic lung disease 8
Key Pitfalls to Avoid
Do not rely solely on pulse oximetry SpO₂ in patients with suspected left-shifted curves (alkalosis, hypothermia, methemoglobinemia, CO poisoning)—pulse oximeters cannot differentiate carboxyhemoglobin from oxyhemoglobin and will report SpO₂ >90% even with COHb ≥25% 8
Avoid sudden cessation of supplemental oxygen in patients who developed hypercapnic respiratory failure on high-concentration oxygen—rebound hypoxemia can be fatal and oxygen should be stepped down gradually with continuous saturation monitoring 7
In mechanically ventilated COPD patients, rapid correction of respiratory acidosis through the Bohr effect can cause a persistent left shift (lower in vivo P50 of 22.7 vs. 25.8 torr in non-ventilated patients), potentially impairing oxygen delivery despite improved blood gases 4
Stored blood for transfusion has depleted 2,3-DPG levels causing a left shift, though levels return to ~50% of normal after 6 hours and normalize within 48 hours post-transfusion 8