Hypoxemia


Definitions

Respiratory Failure (see Respiratory Failure)

  • Definition
    • Respiratory Failure is Defined as the Occurrence of One or Both of the Following
      • Decreased pO2, as Predicted for the Patient’s Age (Hypoxemia)
      • Increased pCO2 (Hypercapnia) in the Setting of a Normal Serum Bicarbonate
        • A Normal Serum Bicarbonate is Specified Here Since a Primary Metabolic Alkalosis (with Increased Serum Bicarbonate) Would Be Expected to Result in a Normal Compensatory Increase in pCO2: this normal compensatory mechanism functions to maintain a normal serum pH and would not be considered “respiratory failure”

Hypoxemia (see Hypoxemia)

  • Definition
    • Hypoxemia is Defined a Decrease in Hemoglobin Oxygen Saturation (as Assessed by Pulse Oximetry: SaO2 or SpO2) or Decrease in Arterial pO2 (as Assessed by Arterial Blood Gas)
  • Note that a Patient May Be Hypoxemic, But Not Be Hypoxic
    • Example
      • A Young Hypoxemic Patient Can Significantly Increase Their Cardiac Output to Maintain Tissue Oxygen Delivery

Hypoxia (see Hypoxemia)

  • Definition
    • Hypoxia is Defined as a State of Impaired Tissue Oxygenation
  • Note that a Patient May Be Hypoxic, But Not Be Hypoxemic
    • Example
      • In Cyanide Intoxication, SaO2 Can Be Normal, But Tissues May Be Hypoxic (see Cyanide)

Anoxia

  • Definition
    • Anoxia is Defined as Complete Tissue Deprivation of Oxygen Supply

Hypercapnia (see Hypercapnia)

  • Definition
    • Hypercapnia is Defined as Increase in Arterial pCO2 (i.e. Increased Arterial Blood Partial Pressure of Carbon Dioxide) to >40 mm Hg

Acidemia

  • Definition
    • Acidemia is Defined as Decrease in Arterial pH < 7.40 (Due to Either Metabolic or Respiratory Acidosis)
  • Note that a Patient Can Be Acidemic without having a Respiratory Acidosis
    • Example
      • Metabolic Acidosis Can Produce Acidemia without the Presence of a Respiratory Acidosis

Alkalemia

  • Definition Alkalemia is Defined an Increase in Arterial pH to >7.40 (Due to Either Metabolic or Respiratory Alkalosis)

Acidosis

  • Definition
    • Acidosis is Defined as the Presence of an Acid-Producing Acid-Base Disturbance (with or without Concomitant Acidemia)
  • Clinical Scenarios in Which an Acidosis is Present, But in Which the pH is Not Acidemic
    • Presence of a Metabolic Acidosis May Not Necessarily Result in an Acidemic pH (pH <7.4), Since Respiratory Compensation (Hyperventilation) Occurs, Resulting in an Increase in the Serum pH
    • Presence of a (Chronic) Respiratory Acidosis May Not Necessarily Result in an Acidemic pH (pH <7.4), Since Metabolic Compensation (Renal Bicarbonate Retention) Generally Occurs Over a Period of Days, Resulting in an Increase in the Serum pH

Alkalosis

  • Definition
    • Alkalosis is Defined as the Presence of an Alkali-Producing Acid-Base Disturbance (with or without Concomitant Alkalemia)
  • Clinical Scenarios in Which an Alkalosis is Present, But in Which the pH is Not Alkalemic
    • Presence of a Metabolic Alkalosis May Not Necessarily Result in an Alkelemic pH (pH >7.4), Since Respiratory Compensation (Hypoventilation) Occurs Rapidly, Resulting in a Decrease in the Serum pH
    • Presence of a (Chronic) Respiratory Alkalosis May Not Necessarily Result in an Alkalemic pH (pH >7.4), Since Metabolic Compensation (Renal Bicarbonate Wasting) Generally Occurs Over a Period of Days, Resulting in a Decrease in the Serum pH

Respiratory Acidosis (see Respiratory Acidosis)

  • Definition
    • Respiratory Acidosis is Defined as a Disorder Which Results in Increase in Arterial pCO2 with an Associated Decrease in Arterial pH
  • Note that a Patient Can Have a Respiratory Acidosis without Being Significantly Acidemic
    • Example
      • Via Normal Compensatory Mechanisms, Chronic Respiratory Acidosis Induces Metabolic (Predominantly Renal) Compensation (with a Increase in Serum Bicarbonate Over Time), Culminating in Minimal Acidemia

Terms

  • PaO2: arterial pO2 (arterial oxygen tension)
    • Usually Referred to Simply as pO2
  • PAO2: alveolar PO2 (alveolar oxygen tension)
  • SpO2: pulse oximetry, as determined by peripheral pulse oximeter (see Pulse Oximetry)
  • SaO2: pulse oximetry, as determined by arterial blood gas co-oximeter (see Arterial Blood Gas)


Physiology of Gas Exchange and Oxygen Delivery

Ventilation/Perfusion (V/Q) Relationships

  • V/Q Matching is Normally Heterogeneous Throughout Various Lung Regions
    • Higher V/Q Ratios are Present in the Lung Apices, as Compared to the Bases
    • The Normal Overall V/Q Ratio of the Lungs is About 0.8
      • Not 1, as One Would Ideally Predict
    • There is Normally a Small Amount of V/Q Mismatch as Part of Normal Human Physiology
  • In Pathologic States, Extreme V/Q Relationships May Occur
    • V/Q = 0: in effect, there is perfusion without ventilation -> termed “shunt”
    • V/Q = Infinity: in effect, there is ventilation without associated perfusion -> termed “dead space”

Alveolar Gas Equation

  • PAO2 = [FIO2 x (Patm – PH2O)] – (pCO2/R)
  • PAO2 = [FIO2 x (760 – 47)] – (pCO2/0.8)
  • Terms
    • PAO2: alveolar PO2 (alveolar oxygen tension)
    • FIO2: fraction of inspired gas which is oxygen
    • Patm: atmospheric pressure
    • PH2O: saturated water vapor pressure
    • pCO2: arterial partial pressure of CO2
    • R: respiratory quotient

Simplified Alveolar Gas Equation

  • Terms
    • PAO2: alveolar PO2 (alveolar oxygen tension)
  • Assumptions
    • FIO2: room air
    • Altitude: sea level
    • Note: arterial PaCO2 (pCO2) is assumed to be nearly the same as alveolar PACO2 in this equation
    • Respiratory Exchange Ratio (RER) = 0.8 (Reflecting a Balanced Diet)
      • Oxidation of a Molecule of Carbohydrate -> RER = 1.0
      • Oxidation of a Molecule of Fatty Acid -> RER = 0.7

Inverse Relationship Between Arterial pCO2 and pO2

  • Assumptions
    • A-a gradient remains the same (in this case, A-a gradient = 10)
    • Respiratory Exchange Ratio (RER) = 0.8 (Reflecting a Balanced Diet)
      • Oxidation of a Molecule of Carbohydrate -> RER = 1.0
      • Oxidation of a Molecule of Fatty Acid -> RER = 0.7

Factors Accounting for the Presence of the Alveolar-Arterial (A-a) O2 Gradient (i.e. Why the A-a Gradient is Not Zero)

  • Small Amount of Physiologic V/Q Mismatch is Normally Present
    • Overall V/Q of the Lungs is About 0.8 (Not 1.0)
    • V/Q Mismatch Increases with Age, Requiring Age-Correction of the Expected A-a Gradient
  • Small Amount of Anatomic Shunt is Normally Present
    • In Normal Health, the Following Two Sources Represent About 2% of the Normal Cardiac Output and Account for About 33% of the Normal A-a Gradient Observed
      • Venous Blood from Bronchial Circulation Drains into the Pulmonary Veins
        • Bronchial Circulation Provides Blood Supply to the Conducting Zone Airways
      • Venous Blood from Coronary Circulation Drains Through the Thebesian Veins into the Left Ventricle

2,3-Bisphosphoglycerate (2,3-BPG)

General Concepts

  • Human Red Blood Cells Normally Have Levels of 2,3-Bisphosphoglycerate (2,3-BPG) Which are 1000x Higher than the Levels Present in Other Cells and Approximately Match the Molar Level of the Hemoglobin Tetramer (NEJM, 2022) [MEDLINE]
  • 2,3-Bisphosphoglycerate (2,3-BPG) is an Intermediate in the Glycolytic Pathway Which Binds to Dexoyhemoglobin and Functions to Lower its Affinity for Oxygen
    • When Hemoglobin is Exposed to Increasing Oxygen Pressure, the Presence of 2,3-BPG Lowers the Fractional Oxygen Saturation, Shifting the Oxygen-Hemoglobin Dissociation Curve to the Right

Anemia Increases Red Blood Cell 2,3-BPG Levels

  • Nearly All Patients with Anemia (Regardless of Etiology) Have Increased 2,3-BPG Levels
    • This Increased 2,3-BPG Shifts the Oxygen-Hemoglobin Dissociation Curve to the Right, Enhancing Oxygen Delivery
      • For Example, an Anemia-Associated Increase in 2,3-BPG Might Increase from 20% of the Oxygen Unloaded to 30% of the Oxygen Unloaded
      • This Enhanced Oxygen Unloading Partially Compensates for the Decrease in Red Cell Mass Which is Seen in the Setting of Anemia

Oxygen-Hemoglobin Dissociation Curve

Sigmoidal Relationship Between Oxygen Saturation (SaO2) and pO2

  • Sigmoidal Shape of the Oxygen-Hemoglobin Dissociation Curve is a Result of Cooperative Binding of Oxygen Molecules to the 4 Binding Sites on Hemoglobin
    • Cooperative Binding: the characteristic of hemoglobin to demonstrate an enhanced ability to bind an oxygen molecule after a subunit has already bound an oxygen molecule
    • Consequences of the Sigmoidal Shape of the Oxygen-Hemoglobin Dissociation Curve
      • With pO2 >60 mmg Hg (Right Flat Portion of the Curve): a large increase in pO2 results in a small increase in SaO2
      • With pO2 <60 mm Hg (Left Steep Portion of the Curve): a small decrease in pO2 results in a large decrease in SaO2
    • Oxygen Loading: occurs in the lungs over the flat portion of curve
      • Due to the Flat Slope in this Region of the Curve, Even if the Alveolar pO2 Decreases (Resulting in a Decrease in Arterial pO2), Hemoglobin Loading with Oxygen Will Be Minimally Affected
    • Oxygen Unloading: occurs at the tissues over the steep portion of curve
      • Due to the Steep Slope of this Region of the Curve, Peripheral Tissues Can Extract a Relatively Large Amount of Oxygen from Hemoglobin with a Small Decrease in Arterial pO2

Factors Which Shift the Oxygen-Hemoglobin Dissociation Curve to the Left

  • General Comments
    • Shift of the Oxygen-Hemoglobin Dissociation Curve to the Left Increases Hemoglobin Affinity for Oxygen and Decreases Oxygen Delivery to Tissues
  • Abnormal Hemoglobin
    • Carboxyhemoglobinemia (see Carboxyhemoglobinemia)
      • Hemoglobin Binds to Carbon Monoxide 200–250x More Avidly than Oxygen
      • Arterial pO2 Remains Normal, But Tissue Hypoxia Occurs
    • Fetal Hemoglobin
      • Fetal Hemoglobin (Which is Composed of Two Alpha and Two Gamma Chains) Has a Higher Affinity for Oxygen than Normal Hemoglobin A (Which is Composed of Two Alpha and Two Beta Chains)
    • Hemoglobin Variants with Decreased Hemoglobin Affinity for 2,3-BPG
      • Hb Rahere (lys82thr)
      • Hb Helsinki (lys82met)
      • Hb Providence (lys82asn—>asp)
    • Hemoglobin Variants with Increased Hemoglobin Affinity for Oxygen
      • Hemoglobin Chesapeake: oxygen affinity studies revealed a whole blood p50 of 19 mmHg (normal: 26 mmHg), normal Bohr effect (increase in oxygen affinity with elevations in pH), and normal 2,3-BPG binding
      • Hemoglobin Montefiore
      • Hemoglobin Heathrow (HBB phe103leu)
    • Methemoglobinemia (see Methemoglobinemia)
      • In Methemoglobinemia, the Iron Center Has Been Oxidized from the Normal +2 Oxidation State to the +3 State
      • Ferric Hemes of Methemoglobin are Unable to Bind Oxygen and Therefore, Result in a “Functional Anemia” with Decreased Oxygen Delivery to Tissues
        • While the Ferric Heme is Unable to Bind Oxygen, the Remaining Three Ferrous Hemes in the Hemoglobin Tetramer Have Increased Avidity for Oxygen, Resulting in Impaired Oxygen Unloading at the Tissues
      • Tissue Hypoxia Occurs
    • Hemoglobin H (Alpha Thalassemia Intermedia) (see Thalassemias)
  • Alkalemia (Increased Serum pH) (see Metabolic Alkalosis)
  • Decreased Red Blood Cell 2,3-Bisphosphoglycerate (2,3-BPG) (Previously Called 2,3-Diphosphoglycerate or 2,3-DPG)
    • The Polyanion, 2,3-BPG is Normally Present within Red Blood Cells and is Formed as a Product of the Glycolytic Pathway
    • 2,3-BPG Binds to Deoxyhemoglobin, Decreasing the Affinity of Hemoglobin for Oxygen
    • Decreased 2,3-BPG Results in a Leftward Shift of the Hemoglobin Dissociation Curve, Increased Hemoglobin Affinity for Oxygen, and Decreased Oxygen Delivery to Tissues
    • Etiology of Decreased 2,3-BPG
  • Decreased Red Blood Cell Mean Corpuscular Hemoglobin Concentration (MCHC)
  • Hypocapnia (see Hypocapnia)
  • Hypothermia (see Hypothermia)

Factors Which Shift the Oxygen-Hemoglobin Dissociation Curve to the Right

  • General Comments
    • Shift of the Oxygen-Hemoglobin Dissociation Curve to the Right Decreases Hemoglobin Affinity for Oxygen and Increases Oxygen Delivery to the Tissues (Bohr Effect)
    • Rightward Shift of the Curve is Advantageous During Exercise, Respiratory Distress, or Prolonged Hypoxia
  • Abnormal Hemoglobin
    • Sickle Cell Disease (see Sickle Cell Disease)
    • Sulfhemoglobinemia (see Sulfhemoglobinemia)
      • Sulfhemoglobin Has Iron in the Ferric State, as Well as a Sulfur Atom Incorporated into the Hemoglobin, Resulting in Impaired Oxygen Carriage
      • However, Counteracting that, Sulfhemoglobin Also Results in a Rightward Shift of the Hemoglobin by Decreasing the Oxygen Affinity of the Remaining Unaffected Hemoglobin, Resulting in Enhanced Oxygen Unloading at the Tissues
      • Although a Patient with Sulfhemoglobinemia May Have a Similar Percentage of Hemoglobin Affected as a Patient with Methemoglobinemia, They are Generally Less Clinically Symptomatic Due to the Counteracting Effect on the Oxygen-Hemoglobin Dissociation Curve
      • Unlike Methemoglobinemia, Sulfhemoglobin Cannot Be Converted Back to Normal Hemoglobin Using Methylene Blue
        • Although Packed Red Blood Cell Transfusion May Be Useful in Some Cases, Sulfhemoglobin is Only Removed from the Affected Red Blood Cells with Elimination of the Red Blood Cell After Their Normal Lifespan of 120 Days
  • Acidemia (Decreased Serum pH) (see Metabolic Acidosis-General)
  • Exercise
  • Hypercapnia (see Hypercapnia)
  • Hyperthermia/Fever (see Fever)
  • Increased Red Blood Cell 2,3-Bisphosphoglycerate (2,3-BPG) (Previously Called 2,3-Diphosphoglycerate or 2,3-DPG)
    • The Polyanion, 2,3-BPG is Normally Present within Red Blood Cells and is Formed as a Product of the Glycolytic Pathway
    • 2,3-BPG Binds to Deoxyhemoglobin, Decreasing the Affinity of Hemoglobin for Oxygen
    • Increased 2,3-BPG Results in a Rightward Shift of the Hemoglobin Dissociation Curve, Decreased Hemoglobin Affinity for Oxygen, and Increased Oxygen Delivery to Tissues
    • Etiology of Increased 2,3-BPG
  • Increased Red Blood Cell Mean Corpuscular Hemoglobin Concentration (MCHC)
  • Propanolol (see Propanolol)
  • Myo-Inositol Trispyrophosphate (ITPP) (Also Known as OXY111A)
    • ITPP is a Medication Which Causes Allosteric Modulation of Red Blood Cell Hemoglobin and was Developed to Decrease Tissue Hypoxia

Oxygen Delivery and Consumption

General Comments

  • Cardiopulmonary Function is Designed to Facilitate the Delivery of Adequate Oxygen to Meet the Demands of Peripheral Tissues
  • Determinants of Adequate Oxygenation at the Tissue Level
    • Oxygen Delivery (in mL O2/min)
    • Tissue Oxygen Consumption (in mL O2/min)

Arterial Oxygen Content Equation

  • Most of the Oxygen Which Diffuses from the Alveolus into the Blood is Bound by Hemoglobin
    • The Amount of Oxygen Dissolved in Plasma is Generally Small Relative to the Amount of Oxygen Bound to Hemoglobin, But Becomes Significant at Very High pO2 (as in a Hyperbaric Chamber) or in the Setting of Severe Anemia
      • The Constant 0.0031 in the Arterial Oxygen Content Equation is the Solubility Coefficient of Oxygen at Body Temperature
      • Because this Amount is Relatively Small, the pO2 Term is Commonly Omitted from the Arterial Oxygen Content Equation (as We Do Below)
    • Under Normal Conditions, Complete Oxygenation of the Blood Occurs in 0.25 sec (This is Approximately One Third of the Total Time that the Blood is in Contact with the Alveolar-Capillary Membrane)
      • This Rapid Diffusion Normally Allows the System to Sufficiently Compensate for Any Impairment in Oxygen Diffusion
    • In Dyshemoglobinemias (Such as Sickle Cell Disease, etc), the Arterial Oxygen Content is Calculated with the Same Equation as Below, Although the Saturations (and Therefore, the Oxygen Content) Will Be Different for a Specific pO2 (Pediatr Pulmonol, 1999) [MEDLINE]
  • Arterial Oxygen Content = [(1.34 x Hb x 10 x SaO2) + (pO2 x 0.0031 x 10)]
    • Constant 1.34 mL O2/g Hb: approximately 1.34 ml of O2 is carried per g of Hb
      • While the Normal Oxygen Carrying Capacity is 1.39 ml O2 per g of Hb, the Presence of Abnormal Hemoglobins (Such as Carboxyhemoglobin and Methemoglobin) Decreases this Value to 1.34 ml O2 per g of Hb
    • Hemoglobin (Hb): in g/dL
    • 10 dL/1L: corrects the units from dL to L
    • Arterial Oxygen Saturation (SaO2): as a decimal
    • pO2: in mm Hg
    • Constant 0.0031 mL O2/L/mm Hg: solubility coefficient of oxygen at body temperature
    • 10 dL/1L: corrects the units from dL to L
    • Normal Arterial Oxygen Content: approximately 200 mL O2/L (or 20 mL O2/dL)
      • Note: This Equation Will Yield the Arterial Oxygen Content in mL O2/L, Which Allows the Arterial Oxygen Content Value to Be Plugged into the Oxygen Delivery Equation Below without Unit Conversion
  • Simplified Arterial Oxygen Content Equation Omitting the Relatively Minor Contribution of the pO2 Term: this is justified, since the amount of dissolved oxygen represents <1% of the arterial oxygen content
    • Arterial Oxygen Content = [1.34 x Hb x 10 x SaO2]

Oxygen Delivery Equation

  • Definition: rate at which oxygen is transported from the lungs to the tissues
    • Using a Train Analogy
      • Hb = number of boxcars
      • SaO2= how full the boxcars are
      • CO = how fast the train is going
    • Note that the Hemoglobin Concentration Significantly Impacts the Oxygen Delivery
      • Example: with a Hb of 20 ml/dl, the oxygen content is twice as much as the oxygen content with a Hb of 10 ml/dl, even though the oxygen saturation and PO2 are the same in both samples
  • Oxygen Delivery = [Arterial Oxygen Content] x CO
  • Oxygen Delivery = [(1.34 x Hb x 10 x SaO2)] x CO
    • Constant 1.34 mL O2/g Hb: approximately 1.34 ml of O2 is carried per g of Hb
      • While the Normal Oxygen Carrying Capacity is 1.39 ml O2 per g of Hb, the Presence of Abnormal Hemoglobins (Such as Carboxyhemoglobin and Methemoglobin) Decreases this Value to 1.34 ml O2 per g of Hb
    • Hemoglobin (Hb): in g/dL
    • 10 dL/1L: corrects the units from dL to L
    • Arterial Oxygen Saturation (SaO2): as a decimal
    • Thermodilution-Measured Cardiac Output from Swan-Ganz Catheter (CO): in L/min
    • Normal Oxygen Delivery (Using Cardiac Output = CO): approximately 1000 mL O2/min
      • Normal Oxygen Delivery (Using Cardiac Index = CI): approximately 550-650 mL/min/m2

Oxygen Consumption Equation

  • Oxygen Consumption = [1.34 x Hb x 10 x (SaO2-SvO2)] x CO
    • Oxygen Consumption: in mL/min
    • Constant 1.34 mL O2/g Hb: approximately 1.34 ml of O2 is carried per g of Hb
      • While the Normal Oxygen Carrying Capacity is 1.39 ml O2 per g of Hb, the Presence of Abnormal Hemoglobins (Such as Carboxyhemoglobin and Methemoglobin) Decreases this Value to 1.34 ml O2 per g of Hb
    • Hemoglobin (Hb): in g/dL
    • 10 dL/1L: corrects the units from dL to L
    • Arterial Oxygen Saturation (SaO2): as a decimal
    • Venous Oxygen Saturation (SvO2): as a decimal
    • Thermodilution-Measured Cardiac Output from Swan-Ganz Catheter (CO): in L/min
    • Normal Oxygen Consumption (Using Cardiac Output = CO): approximately 250 mL O2/min
      • Normal Oxygen Consumption (Using Cardiac Index = CI): approximately 110-130 mL/min/m2
  • Etiology of Increased Oxygen Consumption
    • Catecholamine Release or Administration
    • Exercise
    • Sepsis (see Sepsis)

Fick Equation

  • Fick Cardiac Output = Oxygen Consumption/(10 x Arteriovenous O2 Difference)
  • Fick Cardiac Output = Oxygen Consumption/(10 x Arterial Oxygen Content – Venous Oxygen Content)
  • Fick Cardiac Output = 250/[(1.34 Hb x 10 x SaO2) – (1.34 x Hb x 10 x SvO2)]
    • Oxygen Consumption: this equation assumes the oxygen consumption is approximately 250 mL/min (or determined by respirometry or a nomogram)
    • Arteriovenous O2 Difference: in mL O2/dL
    • Constant 1.34 mL O2/g Hb: approximately 1.34 ml of O2 is carried per g of Hb
      • While the Normal Oxygen Carrying Capacity is 1.39 ml O2 per g of Hb, the Presence of Abnormal Hemoglobins (Such as Carboxyhemoglobin and Methemoglobin) Decreases this Value to 1.34 ml O2 per g of Hb
    • Hemoglobin (Hb): in g/dL
    • 10 dL/1L: corrects the units from dL to L
    • Arterial Oxygen Saturation (SaO2): as a decimal
    • Venous Oxygen Saturation (SaO2): as a decimal

Oxygen Extraction Ratio

  • Oxygen Extraction Ratio = (Arterial Oxygen Content – Venous Oxygen Content)/Arterial Oxygen Content
    • Normal Oxygen Extraction Ratio: approximately 0.25-0.30 (interpretation: only 25-30% of oxygen delivered is taken up by tissues)
  • Increased Oxygen Extraction Ratio
    • Etiology of Increased Oxygen Extraction Ratio
      • Low Cardiac Output State
        • Cardiogenic Shock
        • Hypovolemic Shock
  • Decreased Oxygen Extraction Ratio
    • Etiology of Decreased Oxygen Extraction Ratio
      • Sepsis (see Sepsis): due to peripheral shunting and decreased tissue extraction
      • Hepatopulmonary Syndrome (see Hepatopulmonary Syndrome): due to high CO + low SVR state seen in cirrhosis
  • During States of Increased Metabolic Demand (Exercise, Pregnancy,etc), Oxygenation Consumption Increases Because More Oxygen is Required to Maintain Aerobic Cellular Metabolism
    • This is Achieved by Increasing Both Oxygen Delivery and Oxygen Extraction (Crit Care Clin, 1986) [MEDLINE] (Chest, 1990) [MEDLINE]
    • Oxygen Consumption is Disproportionately Impacted by the Increased Oxygen Extraction, with the Increased Oxygen Delivery Contributing a Small Amount (Chest, 1991) [MEDLINE]
    • Enhanced Oxygen Extraction Appears to Be Mediated at the Capillary Level (Crit Care Clin, 1986) [MEDLINE]
  • Dysregulation of Peripheral Oxygen Extraction Has Been Observed in Patients with Heart Failure with Preserved Ejection Fraction (HFpEF), Leading to Impaired Functional Capacity (Circ Heart Fail, 2015) [MEDLINE]

Oxygen Delivery/Oxygen Consumption Ratio (DO2/VO2 Ratio)

  • Normal Oxygen Delivery/Oxygen Consumption Ratio
    • Homeostatic Mechanisms Normally Maintain an Oxygen Delivery/Consumption Ratio of 5:1
    • Consequently, in the Normal Resting Adult, Only 20% of the Delivered Oxygen is Utilized for Metabolism, Leaving 80% in the Venous Blood
    • During States of Increased Oxygen Consumption (Catecholamine Release/Administration, Exercise, Sepsis, etc), Oxygen Delivery is Increased to Maintain the Oxygen Delivery/Consumption Ratio of 5:1
  • Decreased Oxygen Delivery/Oxygen Consumption Ratio
    • When the Oxygen Delivery/Oxygen Consumption Ratio Decreases Below 2:1 (i.e. 50% Extraction), There is Inadequate Oxygen to Maintain Oxygen-Dependent (Aerobic) Metabolism, Resulting in Switching to Anaerobic Metabolism, Resulting in Lactic Acidosis
    • Anaerobic Metabolism is Tolerated for a Few Hours at Most, and if it Persists, Cardiovascular and Metabolic Collapse May Occur


Etiology of Hypoxemia

Pseudohypoxemia

Processing Artifact

  • Mechanism
    • Arterial Blood Gas (ABG) Left at Room Temperature (Particularly with Severe Leukocytosis), Resulting in In Vitro Oxygen Consumption by White Blood Cells in the Sample
  • Diagnosis
  • Clinical
    • No Clinical Manifestations

Normal A-a Gradient Hypoxemia

Acute/Chronic Hypoventilation

  • Mechanism
    • Per the Simplified Alveolar Gas Equation (Above), Increased Arterial pCO2 (Hypercapnia) Results in an Inverse Decrease in Arterial pO2 (Hypoxemia)
  • Etiology

Decreased Inspired PO2 (PiO2)

  • Mechanism
    • Decreased PiO2 Results in Decreased Oxygen Delivery to the Alveoli (with Decreased Alveolar pO2)
    • PiO2 = FIO2 x (Patm – PH20)
      • Patm: atmospheric pressure
      • PH20: partial pressure of water (equal to 47 mm Hg at 37 degrees C)
  • Etiology
    • Fire in Enclosed Space
    • High Altitude (with Decreased Barometric Pressure)
      • Sea Level (0 ft): FIO2 = 21%, PIO2= 150, pATM = 760, pH2O = 47 (at 37 degree C)
      • Denver (5280 ft): FIO2 = 21%, PIO2= 125, pATM = 640, pH2O = 47 (at 37 degree C)
    • Inadvertent Administration of Low FIO2 During Mechanical Ventilation: due to circuit leak, clinician error, etc

Low Mixed Venous Oxygen Saturation

  • Mechanism
    • Blood Returns to the Right Side of the Heart in a Severely Deoxygenated State and Cardiopulmonary System is Incapable of Re-Oxygenating the Blood
    • Low Mixed Venous Oxygen Saturation Usually Only Results in Arterial Hypoxemia in the Setting of Coexistent Anemia, V/Q Mismatch, or Right-to-Left Shunt
      • These Conditions Result in an Impaired Ability to Re-Oxygenate the Blood
  • Etiology
    • Decreased Cardiac Output State/Cardiogenic Shock (see Cardiogenic Shock)
    • Increased Tissue Oxygen Extraction
      • Anxiety (see Anxiety)
      • Fever (see Fever)
      • Increased Work of Breathing

Elevated A-a Gradient Hypoxemia

Intrapulmonary Right-to-Left Shunt (see Intracardiac and Extracardiac Shunt)

  • Mechanism
    • Shunting of Unoxygenated Blood Through Lung, without Undergoing Oxygenation
    • Note that a Large Intrapulmonary Shunt Can Produce a Region of Near Zero V/Q Ratio
      • In This Respect, Intrapulmonary Shunt Really Represents the Most Extreme Form of V/Q Mismatch
    • Shunt is Classically Characterized by Poor Response of pO2 (or SaO2) to the Administration of Supplemental Oxygen
  • Quantification of Shunt Fraction
    • Perform on 100% FIO2 for at Least 20 min (to Allow Nitrogen Washout)
    • Qs/Qt = (CcO2-CaO2) / (CcO2-CvO2)
      • PIO2 = FIO2 x pATM -> at sea level and on 100% FIO2, PIO2 = 760
      • PAO2 = PIO2 – (PCO2 x 1.25) -> at sea level and on 100% FIO2, PAO2 = 760 – (PCO2 x 1.25)
      • CcO2: end-capillary oxygen content = Hb x 1.39 + (0.003 x PAO2)
      • CaO2: arterial oxygen content = Hb x SaO2 x 1.39 + (0.003 x PaO2)
        • Use values from ABG
      • CvO2: mixed venous oxygen content = Hb x SvO2 x 1.39 + (0.003 x PvO2)
        • Use values from Swan-Ganz Catheter
    • Normal Shunt Fraction: <5%
      • This Accounts for the Normal Physiologic Degree of Anatomical Shunt Which Exists, Due to the Bronchial and Thebesian Circulations
  • Etiology
    • Acute Respiratory Distress Syndrome (ARDS) (see Acute Respiratory Distress Syndrome)
      • Physiology
        • Due to Physiologic Intrapulmonary Shunt
    • Acute Pulmonary Embolism (PE) (see Acute Pulmonary Embolism)
      • Epidemiology
        • Case Report of Patient with Platypnea-Orthodeoxia Due to Bilateral Lower Lobe Pulmonary Emboli (South Med J, 2011) [MEDLINE]
      • Physiology
        • While Intrapulmonary Shunt May Be a Contributor to the Development of Hypoxemia in the Setting of Acute Pulmonary Embolism (Typically with Coexistent Atelectasis), the Major Mechanism of Hypoxemia in Acute Pulmonary Embolism is V/Q Mismatch
    • Atelectasis (see Atelectasis)
      • Physiology
        • Due to Physiologic Intrapulmonary Shunt
    • Hepatopulmonary Syndrome (see Hepatopulmonary Syndrome)
      • Physiology
        • Due to Anatomic Intrapulmonary Shunt (Which Often Increases with the Patient in an Upright Position, Resulting in Orthodeoxia/Platypnea)
    • Intralobar Pulmonary Sequestration (see Pulmonary Sequestration)
      • Epidemiology
        • One Reported Case of This Resulting in an Anatomic Intrapulmonary Shunt
    • Pneumonia
    • Pulmonary Arteriovenous Malformation (AVM) (see Pulmonary Arteriovenous Malformation (AVM))
      • Physiology
        • Due to Anatomic Intrapulmonary Shunt

Intracardiac Right-to-Left Shunt (see Intracardiac and Extracardiac Shunt)

  • Mechanism
    • Shunting of Unoxygenated Blood from the Right to the Left Side of the Heart, Bypassing the Pulmonary Vascular Bed
  • Etiology
    • Acute Pulmonary Embolism (Acute PE) with Right-to-Left Shunt (see Acute Pulmonary Embolism)
      • Physiology
        • Acutely Increased Pulmonary Artery Pressure May Result in New or Exacerbated Right-to-Left Shunt Through a Pre-existing PFO, etc
    • Atrial Septal Defect with Right-to-Left Shunt (see Atrial Septal Defect)
    • Patent Ductus Arteriosus with Right-to-Left Shunt (see Patent Ductus Arteriosus)
    • Patent Foramen Ovale with Right-to-Left Shunt (see Patent Foramen Ovale)
    • Tetralogy of Fallot with Right-to-Left Shunt (see Tetralogy of Fallot)
      • Physiology
        • Ventricular Septal Defect and Pulmonary Artery Stenosis
    • Ventricular Septal Defect (VSD) with Right-to-Left Shunt (see Ventricular Septal Defect)

Worsened V/Q Mismatch (Above Levels Observed as Part of Normal Physiology)

Diffusion Limitation

  • Mechanism
    • Limitation of Oxygen Exchange Across the Pulmonary Capillary Blood-Gas Barrier
      • Thickening of the Alveolar-Capillary Membrane (Associated with Interstitial Fibrosis, Cryptogenic Organizing Pneumonia, Acute Respiratory Distress Syndrome, Asbestos Exposure, etc) Results in Inadequate Red Blood Cell Transit Time in the Pulmonary Circulation, Not Allowing Adequate Equilibration of pO2 Between the Alveolar Gas and Pulmonary Capillary Blood
    • Note that Diffusion Limitation is Absent in Normal Subjects at Rest
  • Etiology
    • Heavy Exercise (Due to Increased Cardiac Output with Decreased Time Available for Oxygen Diffusion)
      • Resulting in Transient Pulmonary Interstitial Fluid Accumulation
      • Effect of Hypoxia
        • Humans Will Frequently Demonstrate Diffusion Limitation in Setting of Normoxia, But Almost All Will Demonstrate Diffusion Limitation in Setting of Hypoxia
      • Race Horses Develop Diffusion Limitation During Severe Exercise (Explaining the Common Practice of Administering Furosemide Prior to Races, with the Goal of Decreasing the Accumulation of High Cardiac Output-Associated Interstitial Pulmonary Edema)
    • Severe Interstitial Lung Disease with Exercise (see Interstitial Lung Disease)
      • Physiology
        • Due to Increased Cardiac Output with Decreased Time Available for Oxygen Diffusion Combined with Thickening of the Alveolar Capillary Membrane


Diagnosis

Pulse Oximetry (see Pulse Oximetry)

  • Hypoxemia

Arterial Blood Gas (ABG) (see Arterial Blood Gas)

  • Hypoxemia

Evaluation of Hypoxemia

Method #1: Using Calculation of the A-a Gradient

  • General Comments: this is the preferred method
  • Step 1: Calculate Alveolar PO2 Using the Simplified Alveolar Gas Equation
    • On Room Air at Sea Level: Alveolar PO2 (PAO2) = 150 – PCO2/0.8
      • Note: Arterial PaCO2 is Assumed to Be Nearly the Same as Alveolar PACO2 in this Equation
      • Respiratory Exchange Ratio (“R”) is Assumed to Be 0.8
        • Diet of Carbohydrate Alone -> R = 1.0
        • Diet of Fat Alone -> R = 0.7
        • Diet of Mixed Carbohydrates + Fats -> R = 0.8
  • Step 2: Use this Alveolar PO2 to then Calculate the A-a Gradient
    • A-a Gradient = Alveolar PO2 (PAO2) – Arterial PO2 (PaO2)
  • Step 3: Compare A-a Gradient to Age-Predicted A-a Gradient (multiple “rule of thumb” calculations are available, as follows, since there are no accepted reference values available for the age-corrected A-a gradient)
    • Predicted A-a Gradient = 0.43 x Age
    • Predicted A-a Gradient = 2.5 + (0.21 x Age)
    • Predicted A-a Gradient = (Age + 4)/4

Method #2: Using Age-Predicted PO2 (Determined from Experimental Data)

  • Compare Room Air PO2 to Predicted PO2 (Acta Physiol Scand, 1966) [MEDLINE]
    • Predicted Room Air PO2 (in a Normal Seated Adult Patient) = 104.2 – (0.27 x Age)


Clinical Manifestations

Clinical Manifestations of Hypoxemia

  • General Comments
    • Hypoxemia May Be Asymptomatic, Since Compensatory Mechanisms (Such as an Increase in Cardiac Output or an Increase in Hemoglobin) May Act to Maintain Tissue Oxygen Delivery and Avoid Hypoxic End-Organ Dysfunction
  • Cardiovascular Manifestations
    • Angina (see Coronary Artery Disease)
    • Arrhythmia
      • Atrial Fibrillation (AF) (see Atrial Fibrillation)
      • Atrial Flutter (see Atrial Flutter)
      • Ventricular Tachycardia (VT) (see Ventricular Tachycardia)
        • Sleep-Disordered Breathing is Associated with an Increased Risk of Nocturnal Ventricular Arrhythmias (Am J Respir Crit Care Med, 2006) [MEDLINE]
        • In Patients with Heart Failure and Sleep Apnea, Treatment with CPAP Eliminates Sleep-Disordered Breathing and Decreases Ventricular Irritability (Circulation, 2000) [MEDLINE]
      • Ventricular Fibrillation (AF) (see Ventricular Fibrillation)
    • Atrioventricular Heart Block
    • Congestive Heart Failure (CHF) (see Congestive Heart Failure)
    • Hypotension/Pulseless Electrical Activity (PEA) (see Hypotension and Pulseless Electrical Activity)
      • Due to Hypoxia-Induced Systemic Vasodilation (Which Attempts to Maintain Tissue Perfusion with Oxygen Delivery)
    • Prolonged QT Interval (see Torsade)
      • Hypoxemia Has Been Demonstrated to Prolong the QT Interval During Sleep in Patients with Coronary Artery Disease (CAD) (Chest, 1982) [MEDLINE]
      • Nocturnal Hypoxemia Has Been Demonstrated to Prolong the QT Interval in Patients with Chronic Obstructive Pulmonary Disease (COPD) (NEJM, 1982) [MEDLINE]
      • Acute Hypoxia Has Been Demonstrated to Prolong the QT Interval in Normal Subjects (Am J Cardiol, 2003) [MEDLINE]
      • Severe Obstructive Sleep Apnea Has Been Demonstrated to Prolong the QTc Interval in Patients with Congenital Long QT Syndrome (Independent of Age, Sex, BMI, Use of β-Blockers, and History of Syncope), Which is a Biomarker for Sudden Cardiac Death (Sleep, 2015) [MEDLINE] (see Obstructive Sleep Apnea)
        • Severity of Obstructive Sleep Apnea (as Represented by the Apnea-Hypoxia Index and Apnea Index During Sleep) is Directly Related to the Degree of QT Prolongation in This Population
        • The Obstructive Sleep Apnea-Related Increase in the QT May Be Mediated by Hypoxic Episodes (Typically Immediately Following the Apnea), Sympathetic Activation (During the Apnea), and/or Vagal Bradyarrhythmias (During the Apnea)
    • Sinus Tachycardia (see Sinus Tachycardia)
  • Neurologic Manifestations
  • Pulmonary Manifestations
  • Other Manifestations
    • Clubbing (see Clubbing): may occur with chronic hypoxemia
    • Cyanosis (see Cyanosis)
    • Polycythemia (see Polycythemia): may occur with chronic hypoxemia

Clinical Manifestations of Hypoxia

  • General Comments
    • Hypoxia is Always Symptomatic (Since it Reflects a State of Impaired Tissue Oxygenation) and is Typically Associated with Laboratory Manifestations of Lactic Acidosis
  • Cardiovascular Manifestations
    • Angina (see Coronary Artery Disease)
    • Arrhythmia
      • Atrial Fibrillation (AF) (see Atrial Fibrillation)
      • Atrial Flutter (see Atrial Flutter)
      • Ventricular Tachycardia (VT) (see Ventricular Tachycardia)
        • Sleep-Disordered Breathing is Associated with an Increased Risk of Nocturnal Ventricular Arrhythmias (Am J Respir Crit Care Med, 2006) [MEDLINE]
        • In Patients with Heart Failure and Sleep Apnea, Treatment with CPAP Eliminates Sleep-Disordered Breathing and Decreases Ventricular Irritability (Circulation, 2000) [MEDLINE]
      • Ventricular Fibrillation (AF) (see Ventricular Fibrillation)
    • Atrioventricular Heart Block
    • Congestive Heart Failure (CHF) (see Congestive Heart Failure)
    • Hypotension/Pulseless Electrical Activity (PAE) (see Hypotension and Pulseless Electrical Activity)
      • Due to Hypoxia-Induced Systemic Vasodilation (Which Attempts to Maintain Tissue Perfusion with Oxygen Delivery)
    • Prolonged QT Interval (see Torsade)
      • Hypoxemia Has Been Demonstrated to Prolong the QT Interval During Sleep in Patients with Coronary Artery Disease (CAD) (Chest, 1982) [MEDLINE]
      • Nocturnal Hypoxemia Has Been Demonstrated to Prolong the QT Interval in Patients with Chronic Obstructive Pulmonary Disease (COPD) (NEJM, 1982) [MEDLINE]
      • Severe Obstructive Sleep Apnea Has Been Demonstrated to Prolong the QTc Interval in Patients with Congenital Long QT Syndrome (Independent of Age, Sex, BMI, Use of β-Blockers, and History of Syncope), Which is a Biomarker for Sudden Cardiac Death (Sleep, 2015) [MEDLINE] (see Obstructive Sleep Apnea)
        • Severity of Obstructive Sleep Apnea (as Represented by the Apnea-Hypoxia Index and Apnea Index During Sleep) is Directly Related to the Degree of QT Prolongation in This Population
        • The Obstructive Sleep Apnea-Related Increase in the QT May Be Mediated by Hypoxic Episodes (Typically Immediately Following the Apnea), Sympathetic Activation (During the Apnea), and/or Vagal Bradyarrhythmias (During the Apnea)
      • Acute Hypoxia Has Been Demonstrated to Prolong the QT Interval in Normal Subjects (Am J Cardiol, 2003) [MEDLINE]
    • Sinus Tachycardia (see Sinus Tachycardia)
  • Neurologic Manifestations
  • Pulmonary Manifestations
  • Other Manifestations
    • Clubbing (see Clubbing): may occur with chronic hypoxemia
    • Cyanosis (see Cyanosis)
    • Polycythemia (see Polycythemia): may occur with chronic hypoxemia


Treatment of Hypoxemia

Supplemental Oxygen (see Oxygen)

  • See Oxygen

Noninvasive Positive-Pressure Ventilation (NIPPV) (see Noninvasive Positive-Pressure Ventilation)

  • See Noninvasive Positive-Pressure Ventilation

Invasive Mechanical Ventilation (see Invasive Mechanical Ventilation-General)

  • See Invasive Mechanical Ventilation-General


References

General

Physiology

Etiology

Pseudohypoxemia

Clinical Manifestations

Cardiovascular Manifestations

Treatment

General

High-Flow Nasal Cannula (see Oxygen)