Oxygen Physiology

Introduction

• Oxygen is required for aerobic respiration and energy production in cells.¹
  • Oxygen acts as the terminal electron acceptor in the mitochondrial electron transport chain, enabling the production of adenosine triphosphate (ATP) through oxidative phosphorylation.¹
• Atmospheric air contains 21% oxygen.^2,3
• At sea level, the total atmospheric pressure is 760 mmHg, with a partial pressure of oxygen (PO₂) of 160 mmHg.^1,2

The Oxygen Cascade

• The oxygen cascade describes the flow of oxygen from areas with high PO₂ to areas of lower PO₂ (Figure 1).¹
  • Physiologically, this represents the progressive reduction in PO₂ from the atmosphere to the alveoli, arterial blood, peripheral tissues, and finally to the mitochondria.¹

• In the lungs, PO₂ decreases from 160 mmHg in atmospheric air to approximately 100 mmHg in the alveoli.^1,2
  • Air is humidified as it reaches the trachea, and the pressure of inspired oxygen (PiO₂) is lowered to approximately 150 mmHg due to the effects of water vapor pressure.¹
  • The decrease in pressure at the alveoli is influenced by dilution of oxygen with expired CO₂.²
• PO₂ is lowest at the level of the mitochondria, with pressures ranging from 3.8 to 22.5 mmHg depending on the tissue.¹
• Alveolar Gas Equation: Alveolar oxygen pressure (PAO₂) is calculated using the alveolar gas equation.

• At sea level, the atmospheric pressure is 760 mmHg, and the vapor pressure of water at body temperature is 47 mmHg.
• The respiratory quotient (RQ) represents the ratio of CO₂ production to O₂ consumption and is typically set at 0.8.²
• For example, breathing room at sea level would result in a P_AO₂ of (760-47) 0.21- 40/0.8 or 99.7 mmHg, whereas breathing 100% oxygen at sea level will result in a P_AO₂ of (760-47) 1- 40/0.8 or 663 mmHg.
• With increasing altitude, the atmospheric pressure decreases, and as a result, P_AO₂ decreases. Breathing 100% oxygen at the top of Mount Everest (atmospheric pressure of 263 mmHg) will result in a P_AO₂ of (263-47)1.0- 40/0.8 or 166 mmHg.

The Alveolar-Arterial Gradient

• The alveolar-arterial (A-a) gradient measures the difference between the partial pressure of oxygen in the alveoli (P_AO₂) and the partial pressure of oxygen in the arterial blood (P_aO₂).^1-3
• The A-a gradient indicates the efficiency of oxygen transfer from the alveoli to the bloodstream.^1-3
  • A normal A-a gradient is less than 15 mmHg but can increase with aging and respiratory pathology.²
• The etiology of arterial hypoxemia can be classified based on the A-a gradient.³
  • Alveolar hypoventilation is a common cause of hypoxemia with a normal A-a gradient.³
  • Abnormal diffusion capacity and ventilation-perfusion (V/Q) mismatch represent common causes of hypoxemia with an elevated A-a gradient.³
• Alveolar ventilation (V_A) is determined by the respiratory rate, the tidal volume (V_T), and dead space (V_D), and is shown by the equation:^2,3

• Alveolar hypoventilation is evident by a decrease in P_AO₂ and P_aO₂ with an increase in P_aCO₂.³
  • Alveolar hypoventilation can be caused by respiration depression from sedation, respiratory muscle weakness, and obstructive airway disease.³
• The ventilation/perfusion (V/Q) ratio evaluates lung function by comparing the amount of air reaching the alveoli (ventilation) to the amount of blood reaching the alveoli (perfusion).^2,3
  • Intrapulmonary shunting, indicated by a low V/Q ratio, decreases PaO2 because blood bypasses ventilated alveoli and returns to the heart unoxygenated; common causes include atelectasis and pneumonia.^2,3
  • Physiologic dead space, indicated by a high V/Q ratio, decreases P_aO₂ due to inadequate blood flow to ventilated alveoli, which impairs oxygen transfer into the bloodstream; common causes include pulmonary embolism and emphysema.^2,3
• Diffusing capacity (DLO₂) indicates the efficiency of oxygen transfer across the alveolar-capillary membrane.²
  • Diffusing capacity is measured by the carbon monoxide diffusion capacity (DLCO), with reductions in DLCO indicating poor gas transfer across the alveolar-capillary membrane. It can be seen in extensive alveolar destruction.²

Oxygen Transport in Blood

• Oxygen is carried in the blood in two forms: reversibly bound to hemoglobin and dissolved in plasma.^1-3
  • Most oxygen is carried by hemoglobin, with less than 2% dissolved in the plasma.³
• Hemoglobin is the oxygen-carrying molecule found in red blood cells.
  • Hemoglobin has a quaternary structure made up of four heme groups and four protein subunits, with each heme group containing divalent iron (Fe²⁺) that binds oxygen (Figure 2).^1,2
  • Each hemoglobin molecule can carry up to four oxygen molecules, with each gram of hemoglobin theoretically transporting up to 1.39 mL of oxygen.^1,2

• The oxygen–hemoglobin dissociation curve (or oxygen dissociation curve) plots the percentage of hemoglobin saturation at different oxygen tensions, illustrating how blood carries and releases oxygen (Figure 3).^1,2
• Hemoglobin exhibits cooperative binding, where the binding of the first oxygen molecule induces a conformational change, increasing the affinity for additional oxygen molecules. This cooperative binding is evident in the sigmoidal shape of the dissociation curve.^1,2
  • The steep portion of the curve, between 25% and 100% saturation, shows accelerated oxygen binding secondary to cooperative binding, with PO₂ values of 20–40 mmHg facilitating the most efficient oxygen release to tissues.^1,2
  • As hemoglobin nears 90% saturation, fewer available binding sites cause the curve to flatten until full saturation is reached.²
• The P₅₀ value is the PO₂ at which hemoglobin is 50% saturated with oxygen. In a normal adult, the P₅₀ is 26.6 mmHg at 37°C and a pH of 7.4.^1,2
• Fetal hemoglobin has a P₅₀ of 18-19 mmHg due to a higher affinity for oxygen, leading to a low P₅₀ in neonates.⁴ As fetal hemoglobin decreases, P₅₀ increases to about 30 mmHg around ten months of age. It then gradually decreases to adult levels by adolescence.
• A right shift in the curve (increased P₅₀) enhances oxygen release to tissues, while a left shift (decreased P₅₀) reduces oxygen release.^1,2
• Hydrogen ion concentration (Bohr effect), CO² pressure (Haldane effect), temperature, and 2,3-diphosphoglycerate (2,3-DPG) concentration all influence oxygen binding to hemoglobin and can shift the oxygen dissociation curve (Table 1).^1,2
  • 2,3-DPG is a byproduct of anaerobic metabolism and an allosteric effector of hemoglobin. Increased concentration of 2,3-DPG is commonly seen as a physiological adaptation in chronic anemia.²
  • The Bohr effect describes how CO₂ and hydrogen ions affect hemoglobin’s affinity for oxygen. The higher CO₂ content of venous capillary blood decreases hemoglobin’s affinity for oxygen, facilitating oxygen’s release to the tissues. Conversely, lower CO₂ in alveolar capillaries increases hemoglobin’s affinity for oxygen, facilitating oxygen uptake in the alveoli.²
  • The Haldane effect describes oxygen’s ability to influence hemoglobin’s affinity for CO² and hydrogen ions. Deoxygenated hemoglobin has a higher affinity for CO², whereas oxygenated hemoglobin has a lower affinity for CO². This effect promotes the release of CO² from the tissues to the blood and from the blood to the lungs.
  • Together, these effects maximize oxygen delivery and CO² uptake.

• CADET face right is a popular mnemonic for remembering the factors that affect the oxygen-hemoglobin dissociation curve.
  • C – CO₂
  • A – acidosis
  • D – 2,3-DPG
  • E – exercise
  • T – temperature
• Therefore, hypercarbia, acidosis, increased 2,3 DPG, exercise, and hyperthermia cause the oxygen-hemoglobin dissociation curve to shift rightward, making it easier for oxygen to be released to the tissues.
• The concentration of dissolved oxygen in plasma is directly proportional to its partial pressure, resulting in a linear relationship, as described by Henry’s law.^1,2

Oxygen Content and Delivery

• The oxygen content of arterial blood (CaO_₂) is the sum of oxygen dissolved in plasma and bound to hemoglobin. It can be calculated using hemoglobin concentration (Hb) in g/dL, hemoglobin saturation (SaO_₂), the oxygen-carrying capacity of hemoglobin (1.31 mL O_₂/g), and the solubility of oxygen in plasma (0.003 mL O₂/dL/mmHg), as shown by the equation:^1,2

• Oxygen delivery (DO_₂) to tissues is calculated as the product of cardiac output (CO) per minute and CaO₂, and is represented by the equation:^1,2

• • For a resting adult, a normal DO_₂ is approximately 1000 mL O_₂/min.^1,2

Oxygen Consumption, Extraction, and Physiological Supply

• Oxygen consumption (VO₂) is calculated from the product of cardiac output and the difference between arterial oxygen content (CaO₂) and venous oxygen content (CvO₂). This is represented by the Fick equation:^1,2

• • For a resting adult, a normal VO_₂ is approximately 250 mL O_₂/min. This indicates that only 25% of the delivered oxygen is used, with the remaining 75% serving as a reserve for increased demand.^1,2
• Increased oxygen demand (VO_₂) is met by a combination of higher cardiac output and enhanced oxygen extraction from the blood.^1,3
  • Moderate reductions in oxygen delivery generally do not significantly impact oxygen consumption due to compensatory increased oxygen extraction, which lowers mixed venous O_₂ saturation. This is known as supply-independent oxygenation.^1,3
  • Once oxygen delivery decreases below a critical level (DO_₂crit), oxygen consumption will decrease because the oxygen supply can no longer meet the tissue’s oxygen demand. This represents supply-dependent oxygenation and leads to reliance on anaerobic metabolism and lactic acidosis.^1-3
• Physiologic oxygen stores include the oxygen in the lungs, bound to hemoglobin or in tissues, and dissolved in plasma.^2,4
  • Oxygen stores are essential during interruptions in supply, such as apnea, as their depletion can result in hypoxemia within about 90 seconds.²
  • Ventilation with 100% oxygen substantially increases the oxygen content in the lungs, delaying the onset of hypoxemia during apnea to 4 to 5 minutes. This principle underlies preoxygenation strategies before anesthesia induction (Table 2).^2,5

Mixed Venous Oxygen Saturation

• Mixed venous oxygen saturation (SvO₂) reflects the overall balance between oxygen supply and demand by representing the average venous saturation from all organs. SvO₂ does not provide information about oxygenation in individual organs.^2,3
• A normal SvO₂ ranges from 65-75%, indicating a tissue oxygen extraction of 25-35%.³
  • Accurate measurement requires sampling from the pulmonary artery via a Swan-Ganz catheter.
• SvO₂ can be calculated using a modified form of the Fick equation:²

• SvO₂ has diagnostic value in identifying underlying issues with oxygen delivery and consumption (Table 3).²
  • A decrease in SvO₂ signals that compensatory mechanisms (increased cardiac output or arterial oxygen content) are failing to meet the body’s oxygen demands.^2.3

Oxygen Toxicity

• Oxygen toxicity can occur with either acute or chronic exposure to high oxygen concentrations, potentially leading to cell damage and death.⁶
• Acute oxygen toxicity primarily affects the central nervous system, with symptoms such as muscle twitching, tinnitus, nausea, and seizures.⁶
  • The risk for acute oxygen toxicity is increased at high oxygen pressures, including hyperbaric oxygen therapy.⁶
• Pulmonary effects are related to chronic oxygen toxicity.⁶
  • Chronic exposure to oxygen-derived free radicals is believed to damage cell membranes and disrupt protein synthesis, leading to pulmonary edema and fibrosis.⁶
• The fraction of inspired oxygen (FiO₂) can be kept below 0.8 to reduce the risk of oxygen toxicity and the chance of developing pulmonary fibrosis.3