Oxygen and Carbon Dioxide Physiology

Oxygen

• Oxygen (O_2) is a colorless, odorless reactive gas comprising about 20.95% of Earth's atmosphere and is essential for life.
• Human tissues use approximately 250 mL of oxygen per minute and produce 200 mL of carbon dioxide per minute.

Oxygen Dissolution in the Plasma

• Oxygen enters the lungs, crosses the alveolar-capillary membrane, and is transported via:
  • Dissolved oxygen in the plasma.
  • Chemically and reversibly bound to hemoglobin.
• The relationship between these two transport mechanisms is linear; as dissolved oxygen increases, oxygen bound to hemoglobin increases proportionally.
• Henry's Law of Solubility explains oxygen dissolution in plasma:
  • The amount of oxygen dissolved is directly proportional to the partial pressure of oxygen in the alveoli at a given temperature.
  • At 37°C, 0.003 mL of oxygen dissolves in 100 mL of blood, which is insufficient for tissue needs. Most oxygen is transported by hemoglobin.

Oxygen Bound to Hemoglobin

• Erythrocytes contain hemoglobin (Hb), a protein with four polypeptide chains, each containing an iron atom bound to a heme group.
• Adult hemoglobin consists of two alpha-polypeptide chains (141 amino acids each) and two beta-polypeptide chains (146 amino acids each).
• Changes in the number or position of amino acids in these chains can alter hemoglobin's oxygen-carrying ability due to genetic factors, medications, or toxins.
• Sickle Cell Disease Example:
  • Normal alpha-polypeptide chains.
  • Abnormal beta-polypeptide chains with valine at position 6 instead of glutamic acid, resulting in sickle cell hemoglobin (HbS).
• Each erythrocyte contains 270 to 300 million hemoglobin molecules.
• Adequate hemoglobin levels and oxygen saturation are vital for normal tissue oxygenation.
• Oxyhemoglobin: Hemoglobin bound to oxygen.
• Deoxyhemoglobin: Hemoglobin not bound to oxygen (also called reduced or unsaturated hemoglobin).
• Hemoglobin concentration is expressed as grams per deciliter (g/dL) or gram percent (g% Hb).
• Healthy individuals' erythrocytes carry ≈ 20 mL of oxygen per 100 mL of blood, about four times the resting oxygen need.
• Arterial and venous saturation levels differ due to tissue oxygen use.

Calculating Hemoglobin's Oxygen-Carrying Capacity

• Total capacity calculation:
  • Given 1 g of hemoglobin carries 1.34 mL of oxygen, for a hemoglobin level of 15 g% Hb at 100% saturation:
    15
    ewline g\%
    ewline Hb × 1.34
    ewline mL
    ewline O2 = 20.1 ewline vol\% ewline O2
• Multiply the total capacity by the percentage of saturation:
  • If capacity is 20.1 vol% and arterial blood saturation (SaO2) is 97%:
    97\% × 20.1
    ewline vol\%
    ewline O2 = 19.5 ewline mL/dL ewline of ewline O2
• Venous blood sample calculation (e.g., 65% saturation):
  • Given 1 g of hemoglobin carries 1.34 mL of oxygen and hemoglobin level is 15 g%:
    15
    ewline g\%
    ewline Hb × 1.34
    ewline mL
    ewline O2 = 20.1 ewline vol\% ewline O2
  • Then, multiply total capacity by the saturation percentage:
    65\% × 20.1
    ewline vol\%
    ewline O2 = 13 ewline mL/dL ewline of ewline O2
• Mixed Venous Oxygen Level (SvO2):
  • Assesses tissue oxygen delivery.
  • Measured via a pulmonary artery catheter in critically ill patients.
  • Indicates the percentage of oxygen bound to hemoglobin returning to the left side of the heart after circulation.
  • Normal SvO2: 60–80%.
  • Used to evaluate if cardiac output and oxygen delivery meet the body's needs.
  • Measured before and after changes in cardiac medications or mechanical ventilation.
  • Central Venous Oxygen Saturation (ScvO2):
    • Similar assessment using blood from internal jugular or subclavian catheters.
    • Normal value: >70%.

Normal Hemoglobin and Hematocrit Levels

• Adequate hemoglobin levels are essential for tissue oxygenation.
  • Anemia: Abnormally low hemoglobin levels.
  • Polycythemia: Abnormally high hemoglobin levels.
• Complete Blood Count (CBC) is used to assess hemoglobin levels.
• Normal Hemoglobin Levels:
  • Men: 13.8–17.2 g/dL
  • Women: 12.1–15.1 g/dL
  • Infants: 9.5–13 g/dL
  • Newborns: 14–24 g/dL
• Hematocrit (HCT):
  • Measures the volume of erythrocytes compared to total blood volume.
  • Sample obtained via CBC or fingerstick.
• Normal Hematocrit Levels:
  • Men: 40.7–50.3%
  • Women: 36.1–44.3%
  • Infants (1 year): 29–41%
  • Newborns: 55–68%

Oxyhemoglobin Dissociation Curve

• Graphic representation of the oxygen saturation of hemoglobin (SO2) and the partial pressure of oxygen in the blood (PO2).
• Reflects how readily oxygen binds to and releases from hemoglobin molecules (hemoglobin-oxygen affinity).
• Plots SO2 on the y-axis and PO2 on the x-axis.
• Sigmoidal (S-shaped) curve due to the interaction of bound oxygen molecules with additional oxygen molecules.
• Shape changes in the hemoglobin molecule as oxygen molecules bind, facilitating subsequent oxygen binding.
• Conversely, as oxygen is released, the shape change makes further release more difficult.
• Cooperative Binding: Interaction between oxygen and hemoglobin molecules.
• As PO2 increases, more oxygen binds to hemoglobin, causing a steep upward slope from 0 to 60 mm Hg, illustrating oxygen binding and increased arterial oxygen levels.
• The curve flattens at pressures > 60 mm Hg because hemoglobin is 90% saturated at 60 mm Hg.
• From 60 to 100 mm Hg, the curve remains relatively flat as the oxygen content of the blood does not significantly change.
• P50: The point at which hemoglobin is 50% saturated.
  • Normal P50: 26.7 mm Hg.
  • A right shift indicates reduced hemoglobin affinity for oxygen and increased oxygen release to tissues, increasing the P50.
  • A left shift indicates increased hemoglobin affinity for oxygen and decreased oxygen release to tissues, decreasing the P50.

Factors That Can Shift the Oxyhemoglobin Dissociation Curve

• Changes in pH, PaCO2, 2,3-bisphosphoglycerate (2,3-BPG) levels, and body temperature.
• pH Changes:
  • Increased H+ concentration decreases blood pH, resulting in more oxygen release at the tissue level (right shift).
  • Decreased H+ concentration increases blood pH, resulting in more oxygen uptake in the lungs (left shift).
• PaCO2 Changes:
  • Increased PaCO2 increases H+ concentration, decreases pH, and shifts the curve to the right.
  • Decreased PaCO2 decreases H+ concentration, increases pH, and shifts the curve to the left.
  • These changes are related to the Bohr effect.
• Temperature Changes:
  • Increased body temperature shifts the curve to the right (greater oxygen delivery to tissues).
  • Decreased body temperature shifts the curve to the left.
  • Conditions like exercise or fever cause a right shift.
• 2,3-BPG Levels:
  • 2,3-BPG is a byproduct of anaerobic erythrocyte metabolism that alters hemoglobin's oxygen affinity by binding with hemoglobin.
  • Increased 2,3-BPG shifts the curve to the right.
  • Elevations occur at high altitudes, in anemia, chronic lung diseases, or hypoxia.
  • Stored blood has low 2,3-BPG levels, which can reduce oxygen release at the cellular level in transfusion recipients.
• Fetal Hemoglobin (HbF):
  • Low affinity for 2,3-BPG and higher binding affinity for oxygen due to two gamma chains and two beta chains.
  • Binding sites for 2,3-BPG are different in gamma chains, so oxygen does not have to compete with 2,3-BPG for a binding site.
  • Promotes oxygen transport across the placenta.
  • Fetal oxyhemoglobin dissociation curve is positioned farther to the left than the adult curve.
  • Present in newborns and gradually diminishes during the first year of life.

Chromosomes

• Made up of deoxyribonucleic acid (DNA).
• DNA is a twisted double-helix strand made up of four nitrogenous bases: cytosine, adenine, thymine, and guanine.
• These bases are arranged in sequences along the strand to create a specific sequence called a gene.
• Humans have 23 pairs of chromosomes; one half of each pair is inherited from each parent.
• Twenty-two pairs are the same in both sexes.
• The 23rd pair determines gender: females have two X chromosomes, males have one X and one Y chromosome.
• The chromosome inherited from each parent affects the manifestation of disease. Example:
  • Sickle cell trait: Inheriting one normal and one mutated beta-globin gene.
  • Sickle cell disease: Inheriting mutated beta-globin genes from both parents.

Anemia

• Condition in which an abnormally low level of hemoglobin and/or low hematocrit is identified in the blood.
• Hemoglobin levels below 13 g/dL in men or 12 g/dL in women are diagnostic.
• Types of anemia:
  • Iron-deficiency anemia: Insufficient iron for hemoglobin to bind with oxygen.
  • Vitamin deficiency anemia: Insufficient folate and vitamin B12 to produce healthy erythrocytes.
  • Aplastic anemia: Damage or suppression of bone marrow, resulting from radiation/chemotherapy, viral infections, autoimmune diseases, or toxic chemicals.
  • Hemolytic anemia: Erythrocytes are destroyed faster than bone marrow can replace them.
  • Anemia of chronic disease: Chronic disease suppresses erythrocyte development, caused by cancer, HIV/AIDS, inflammatory diseases, or kidney disease.
• Symptoms: Weakness, shortness of breath, dizziness, tachycardia, headache, cold extremities, pallor, and/or chest pain.

Polycythemia

• Also called erythrocytosis, is an abnormal elevation in the amount of hemoglobin in the blood or the hematocrit.
• Hemoglobin levels > 16.5 g/dL (10.3 mmol/L) in men or > 16.0 g/dL (10.0 mmol/L) in women are diagnostic.
• Types:
  • Increase in erythrocytes due to a reduction in plasma volume.
  • Increase in erythrocyte volume due to increased production.
• Classifications:
  • Primary disease of unknown cause.
  • Secondary condition associated with respiratory diseases (COPD, cystic fibrosis), chronic hypoxia, cardiovascular disorders (congestive heart failure), or cancer.
• Symptoms: Fatigue, itching, headache, sweating, blurred vision, burning/numbness of hands/feet, bleeding gums, heavy bleeding, bone pain, shortness of breath, abdominal pain, dizziness, vertigo, insomnia, angina, and/or tinnitus.
• Enlarged spleen may cause pain or discomfort in the left abdomen and feeling full after eating very little.

Cyanosis

• Bluish-gray tint to the skin and/or mucous membranes due to low blood oxygen levels.
• Peripheral cyanosis: Affects extremities (fingertips, toes, palms, feet).
• Central cyanosis: Affects the trunk of the body, face, lips, and tongue.
• Differential cyanosis: Occurs in infants with patent ductus arteriosus, with bluish lower body and pink upper body.

Hypoxemia and Hypoxia

• Hypoxemia: Low level of oxygen in the blood (PaO2).
• Hypoxia: Low level of oxygen in the tissues.
• Symptoms: Cyanosis, shortness of breath, tachycardia, and tachypnea.
• Types of Hypoxia:
  • Hypoxic hypoxia: Low PaO2 caused by hypoventilation, altered diffusion, ventilation-perfusion mismatch, or pulmonary shunting. The body compensates by increasing cardiac output.
  • Anemic hypoxia: Inability of erythrocytes to carry oxygen due to hemoglobin abnormality (sickle cell disease), anemia, or significant blood loss.
  • Circulatory hypoxia: Inadequate PaO2 due to decreased cardiac output or arterial-venous shunting.
  • Histotoxic hypoxia: Exposure to a toxic substance (e.g., cyanide) prevents tissues from using oxygen despite normal delivery.

Oxygen Calculations

• PaO2 and SaO2 are reported with arterial blood gas (ABG) results.

• Arterial Oxygen Content (CaO2):

  • Total number of oxygen molecules in arterial blood, both bound and unbound to hemoglobin.
  • Expressed as volumes percent (vols%).
  • Total volume of oxygen in arterial blood delivered to tissues per unit blood volume.
  • Used with venous oxygen content (CvO2).

• Venous Oxygen Content (CvO2):

  • Amount of oxygen bound to hemoglobin plus oxygen dissolved in plasma, expressed as vols%.
  • Measures the volume of oxygen returning to the lungs from tissues per unit blood volume.
  • Compared to CaO2 to indicate cellular respiration at the tissue level.

• Arterial-Venous O2 Content Difference (C(a–v)O2):

  • The amount of oxygen in arterial blood minus the amount of oxygen in venous blood.
  • Indicates how much oxygen is removed from the blood in the capillaries.
  • Normal value: approximately 5 vol%.
  • Increases when cardiac output decreases or oxygen consumption increases (exercise, seizures, shivering/hypothermia).
  • Decreases when cardiac output rises or oxygen consumption decreases (muscle relaxation, peripheral shunting, hypothermia).

• Calculation:

  C(a–v)O2 = CaO2 - CvO_2

• Total Oxygen Delivery (DO2):

  • Total amount of oxygen delivered to tissues, including dissolved and bound oxygen.
  • Calculated as:

  DO2 = C.O. × CaO2 × 10

  • Where C.O. is the cardiac output, CaO2 is the arterial oxygen content, and 10 adjusts the results from milliliters to liters.
    • Can also use cardiac index (CI) instead of cardiac output.

• Cardiac Output (C.O.): Volume of blood being circulated by the heart.

• Cardiac Index (CI):

  • Assessment of cardiac output relative to a person’s size.
  • Calculated by dividing cardiac output by body surface area.
  • Equation:

  DO2I = CI × CaO2 × 10

CI is the cardiac index, CaO2 is arterial oxygen content, and 10 adjusts the results from milliliters to liters.

• Oxygen Consumption (VO_2):

  • Amount of oxygen being used by the tissues.
  • Calculated as:

  VO2 = Q × (CaO2 - CvO_2) × 10

  • Q: cardiac output, CaO2: arterial oxygen content, CvO2: venous oxygen content, and 10 adjusts the results from milliliters to liters.

• Oxygen Extraction Ratio (ER):

  ER = \frac{VO2}{DO2}

  • Ratio of oxygen consumption to oxygen delivery (also denoted as O2E).

Carbon Monoxide Poisoning

• Carbon monoxide (CO) is a poisonous, odorless, colorless gas from incomplete combustion of carbon-containing materials.
• Consists of one carbon and one oxygen atom.
• Initial symptoms: Shortness of breath, headache, fatigue, dizziness, drowsiness, chest pain, and nausea.
• Prolonged exposure: Vomiting, confusion, loss of consciousness, and muscle weakness.
• CO diffuses into the bloodstream and binds with hemoglobin to form carboxyhemoglobin (COHb).
• COHb prevents oxygen from binding, decreasing PaO2.
• Treatment: Administration of 100% oxygen or hyperbaric oxygen therapy.

Carbon Dioxide

• Composed of a carbon atom covalently double-bonded to two oxygen atoms (CO_2).
• Occurs naturally in the earth's atmosphere and is a by-product of fermentation and cellular respiration.
• 20 times more soluble than oxygen.
• Transported to the lungs for elimination via:
  • Plasma.
  • Erythrocytes.

Transport via Plasma

• Approximately 11% of total CO_2 transport.
  • Dissolved CO_2 (5%).
  • Bicarbonate (HCO_3^-) (5%).
  • Carbamino compounds (less than 1%).
    CO2 + H2O
    ame H2CO3
    ame HCO_3^- + H^+
• Small amount combines with terminal uncharged amino groups (R-NH_2) of amino acids or plasma proteins to form carbamino compounds, regulating blood acid levels.
• CO2 can bind with unbound sites on the alpha and beta chains of hemoglobin to form carbaminohemoglobin.
• This process is reversible by increases in PO2, (CO2 and oxygen have different binding sites on hemoglobin).

Transport via Erythrocytes

• 89% of the total CO_2 transported to the lungs for elimination.
  • 5% dissolves into the intracellular fluid of the erythrocyte.
  • 21% binds inside the erythrocyte to hemoglobin, forming carbaminohemoglobin.
    • One hemoglobin molecule can bind and transport four CO_2 molecules back to the lungs.
    • As carbaminohemoglobin reaches the lungs, the CO_2 is released, and the hemoglobin becomes available for binding with oxygen and is called oxyhemoglobin.
  • The site that CO_2 binds to on hemoglobin is different from the site to which oxygen binds.
  • Carbaminohemoglobin is dark purple/blue color and is the reason deoxygenated venous blood looks dark red in color, veins look bluish under the skin, and the body takes on a bluish tint when hypoxic.
  • Oxyhemoglobin appears bright red in color.
  • 63% of the total CO_2 transported via this pathway.
    • Carbonic anhydrase (CA) converts the CO2 into carbonic acid (H2CO_3).
    • The carbonic acid dissociates into bicarbonate (HCO_3^-) and H^+ ions.
    • The bicarbonate is transported out of the erythrocyte into the plasma of the blood in exchange for a chloride ion (Cl^−). This is called the chloride shift.
    • Bicarbonate is transported via the plasma to the lungs where it is exchanged for the Cl^− ion and moves back into the erythrocyte.
    • Inside the erythrocyte, the H^+ ion dissociates from the hemoglobin and reacts with the bicarbonate.
    • The product of this reaction is a carbonic acid intermediate, which is converted back into carbon dioxide and water through the enzymatic action of carbonic anhydrase.
    • The carbon dioxide produced is released through the lungs during exhalation.

Bicarbonate Buffer System

CO2 + H2O
ame H2CO3
ame H^+ + HCO_3^−

• Allows the majority of CO_2 to be removed from the tissues via the blood with little change to the blood pH levels.
• Regulates CO_2 levels while maintaining the correct pH in the body.

The Bohr and Haldane Effects

• Bohr Effect:
  • Changes in blood PaCO_2 levels causes shifts in the dissociation of oxyhemoglobin.
  • The affinity of hemoglobin for oxygen decreases and favors dissociation of oxyhemoglobin as the partial pressure of carbon dioxide increases.
  • This occurs because the carbon dioxide in the blood reacts with water to form carbonic acid, resulting in a decrease in blood pH, which causes the release of oxygen from hemoglobin at the tissue level.
  • A decrease in carbon dioxide causes a rise in the pH, which results in the hemoglobin picking up more oxygen in the lungs.
• Haldane Effect:
  • Explains the affinity for oxygen and carbon dioxide to hemoglobin.
  • In the absence of oxygen, hemoglobin molecules have a greater affinity for carbon dioxide.
  • At the tissue level, after the oxygen is released, the hemoglobin is more likely to pick up carbon dioxide and transport it to the lungs.
  • Once the carbaminohemoglobin reaches the lungs, the oxygen-rich environment encourages the release of carbon dioxide from the hemoglobin, thereby increasing removal of carbon dioxide from the body.
  • The hemoglobin then picks up the oxygen and carries it back to the tissue.
  • Describes hemoglobin’s ability to carry increased amounts of carbon dioxide in the deoxygenated state as opposed to the oxygenated state.

The Carbon Dioxide Dissociation Curve

• Describes the relationship between PCO2 and the total carbon dioxide concentration in the blood.
• Total carbon dioxide is plotted on the y axis against PCO2 on the x axis.
• The curve is more linear and steeper than the oxygen dissociation curve.
• As total carbon dioxide levels in the blood increase, a linear increase in the PCO2 occurs.
• When the oxygen dissociation curve is overlaid with the carbon dioxide dissociation curve, the Haldane effect on carbon dioxide is illustrated.
• As carbon dioxide saturation decreases, the carbon dioxide concentration increases.
• This is because of the changing affinity of hemoglobin for oxygen and carbon dioxide and the transition back and forth between carboxyhemoglobin and oxyhemoglobin.
• The overlaid curves also show the variances between arterial and venous blood oxygen and carbon dioxide levels.
• The difference in oxygen levels between arterial and venous blood is usually about 60 mm Hg, whereas the differences in carbon dioxide levels is approximately 5 to 7 mm Hg.