• Definition: decreased pO2 or decreased oxygen content in blood
    • Clarification: a patient can be hypoxemic, but not be hypoxic
      • Example: a young hypoxemic patient can significantly increase cardiac output to maintain tissue oxygen delivery
  • Etiology: see below
  • Clinical Manifestations


  • Definition: inadequate tissue oxygenation
    • Clarification: a patient can be hypoxic, but not be hypoxemic
      • Example: in cyanide intoxication, SaO2 can be normal, but tissues may be hypoxic
  • Etiology
    • Decreased Oxygen Delivery
      • Hypoxemia (of Any Etiology): see below
      • Low Cardiac Output (CO) States
      • Carboxyhemoglobinemia (see Carboxyhemoglobinemia, [[Carboxyhemoglobinemia]])
      • Left-to-Right Systemic Shunt: as occurs in sepsis, etc
    • Decreased Tissue Oxygen Uptake
      • Cyanide Intoxication (see Cyanide, [[Cyanide]])
      • Left-Shifted Hemoglobin Dissociation Curve: see below
  • Clinical Manifestations: by the definition of end-organ dysfunction due to inadequate tissue oxygenation, hypoxia ia always symptomatic

Other Terms

  • Anoxia: compelete deprivation of oxygen supply
  • 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
  • SaO2: pulse oximetry, as determined by ABG co-oximeter

Physiology of Gas Exchange and Oxygen Delivery

Oxygen Delivery and Consumption

General Comments

  • Purpose of Cardiopulmonary Function: delivery of adequate oxygen to meet the demands of peripheral tissues
  • Determinants of Adequate Oxygenation at the Tissue Level
    • Amount of Oxygen Delivery
    • Rate of Tissue Oxygen Consumption

Oxygen Carriage in Blood

  • Oxygen Binding to Hemoglobin: most of the oxygen that diffuses from the alveolus into blood is bound by hemoglobin (a small amount of oxygen is dissolved in the plasma)
    • Under normal conditions, complete oxygenation of the blood occurs in 0.25 sec (this is about 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
  • Arterial O2 Content = [Hb x 13.4 x SaO2 x (0.0031 x pO2)] = [Hb x 13.4 x (SaO2)]
    • Hb: in g/dL
    • SaO2: as decimal
    • Note: 1.34 ml of O2 is carried per g of Hb

Oxygen Delivery Equation

  • O2 Delivery = CO x [Hb x 13.4 x (SaO2)]
    • Hb: in g/dL
    • SaO2: as decimal
    • Normal: 1000 mL/min (using CO)
    • Normal: 550-650 mL/min/m2 (using CI)


Oxygen Consumption Equation

  • Oxygen Consumption = CO x [Hb x 13.4 x (SaO2-SvO2)]
    • Hb: in g/dL
    • SaO2: as decimal
    • SvO2: as decimal
    • Normal: 250 mL/min (using CO)
    • Normal: 110-130 mL/min/m2 (using CI)

Oxygen Dissociation Curve

Sigmoidal Relationship Between Oxygen Saturation (SaO2) and pO2

  • Sigmoidal Shape of Oxygen 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
    • Oxygen Loading: occurs in the lungs over the flat portion of curve
    • Oxygen Unloading: occurs at the tissues over the steep portion of curve


  • Consequences of Sigmoidal Shape of the Oxygen Dissociation Curve
    • With pO2 <60 mm Hg (Left Steep Portion of the Curve): small decrease in pO2 results in a large decrease in SaO2
    • With pO2 >60 mmg Hg (Right Flat Portion of the Curve): large increase in pO2 results in a small increase in SaO2

Factors Which Shift Oxygen Dissociation Curve to Right

  • General Comments: shift of curve to the right decreases hemoglobin affinity for oxygen and increases oxygen delivery to tissues (Bohr Effect)
    • Rightward Shift of the Curve is Advantageous During Exercise, Respiratory Distress, or Prolonged Hypoxia
  • Abnormal Hemoglobin
  • Acidosis (see Metabolic Acidosis-General, [[Metabolic Acidosis-General]])
  • Exercise
  • Hypercapnia (see Hypercapnia, [[Hypercapnia]])
  • Hyperthermia/Fever (see Fever, [[Fever]])
  • Increased Red Blood Cell 2,3-Diphosphoglycerate (2,3-DPG)
  • Increased Red Blood Cell Mean Corpuscular Hemoglobin Concentration (MCHC)
  • Propanolol (see Propanolol, [[Propanolol]])

Factors Which Shift Oxygen Dissociation Curve to Left

  • General Comments: shift of curve to the left increases hemoglobin affinity for oxygen and decreases oxygen delivery to tissues
  • Abnormal Hemoglobin
  • Alkalosis (see Metabolic Alkalosis, [[Metabolic Alkalosis]])
  • Carbon Monoxide Intoxication (see Carboxyhemoglobinemia, [[Carboxyhemoglobinemia]])
  • Decreased Red Blood Cell 2,3-Diphosphoglycerate (2,3-DPG)
  • Decreased Red Blood Cell Mean Corpuscular Hemoglobin Concentration (MCHC)
  • Hypocapnia (see Hypocapnia, [[Hypocapnia]])
  • Hypothermia (see Hypothermia, [[Hypothermia]])

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”

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 = 0.8

Inverse Relationship Between Arterial pCO2 and pO2

  • Assumptions
    • A-a gradient remains the same (in this case, A-a gradient = 10)
    • Respiratory Exchange Ratio = 0.8

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)
    • 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

Evaluation of Hypoxemia

Method Using Age-Predicted PO2

  • Compare Room Air PO2 to Predicted PO2
    • Predicted Room Air PO2 = 104.2 – (0.27 x Age)

Method Using Calculation of the A-a Gradient

  • 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
      • The respiratory exchange ratio (“R”) is assumed to be 0.8
        • Diet of carbohydrates 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

Etiology of Hypoxemia


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 O2 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 result in the impaired ability to re-oxygenate the blood
  • Etiology
    • Decreased Cardiac Output State/Cardiogenic Shock (see Cardiogenic Shock, [[Cardiogenic Shock]])
      • Right Ventricular Dysfunction Due to Right Ventricular infarct (see Coronary Artery Disease, [[Coronary Artery Disease]])
      • Acute Cor Pulmonale Due to Acute Pulmonary Embolism (see Acute Pulmonary Embolism, [[Acute Pulmonary Embolism]])
      • Tamponade (see Tamponade, [[Tamponade]]): unclear why this results in decreased mixed venous oxygen saturation
    • Increased Tissue Oxygen Extraction
      • Anxiety (see Anxiety, [[Anxiety]])
      • Fever (see Fever, [[Fever]])
      • Increased Work of Breathing

Increased A-a Gradient Hypoxemia

Worsened V/Q Mismatch

  • Mechanism: worsening of V/Q mismatch, above the levels that are observed as part of normal human physiology
  • Etiology
    • Acute Pulmonary Embolism (Acute PE) (see Acute Pulmonary Embolism, [[Acute Pulmonary Embolism]]): while intrapulmonary shunt may be a contributor to hypoxemia in the setting of acute PE (typically with co-existent atelectasis), the major mechanism of hypoxemia in acute PE is V/Q mismatch
    • Atelectasis (see Atelectasis, [[Atelectasis]])
    • Hemodialysis-Associated Hypoxemia (see Hemodialysis, [[Hemodialysis]])
    • Interstitial Lung Disease (see Interstitial Lung Disease, [[Interstitial Lung Disease]])
    • Leukostasis (see Leukostasis, [[Leukostasis]])
    • Obstructive Lung Disease (see Obstructive Lung Disease, [[Obstructive Lung Disease]]): COPD, asthma, etc
    • Pneumonia (see Pneumonia, [[Pneumonia]])
    • Pulmonary Vascular Disease (see Pulmonary Hypertension, [[Pulmonary Hypertension]])

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

  • Mechanism: shunting of unoxygenated blood through lung, without undergoing oxygenation
    • Note: 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 that exists, due to the bronchial and Thebesian circulations)
  • Etiology
    • Acute Respiratory Distress Syndrome (ARDS) (see Acute Respiratory Distress Syndrome, [[Acute Respiratory Distress Syndrome]]): physiologic intrapulmonary shunt
    • Acute Pulmonary Embolism (PE) (see Acute Pulmonary Embolism, [[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 hypoxemia in the setting of acute PE (typically with co-existent atelectasis), the major mechanism of hypoxemia in acute PE is V/Q mismatch
    • Atelectasis (see Atelectasis, [[Atelectasis]]): physiologic intrapulmonary shunt
    • Hepatopulmonary Syndrome (see Hepatopulmonary Syndrome, [[Hepatopulmonary Syndrome]]): anatomic intrapulmonary shunt (which often increases with the patient in an upright position, resulting in orthodeoxia/platypnea)
    • Intralobar Pulmonary Sequestration (see Pulmonary Sequestration, [[Pulmonary Sequestration]]): one reported case of this resulting in an anatomic intrapulmonary shunt
    • Pneumonia (see Pneumonia, [[Pneumonia]]): physiologic intrapulmonary shunt
    • Pulmonary Arteriovenous Malformation (AVM) (see Pulmonary Arteriovenous Malformation (AVM), [[Pulmonary Arteriovenous Malformation]]): anatomic intrapulmonary shunt

Intracardiac Right-to-Left Shunt (see Intracardiac and Extracardiac Shunt, [[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, [[Acute Pulmonary Embolism]]): 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, [[Atrial Septal Defect]])
    • Patent Ductus Arteriosus with Right to Left Shunt (see Patent Ductus Arteriosus, [[Patent Ductus Arteriosus]])
    • Patent Foramen Ovale with Right to Left Shunt (see Patent Foramen Ovale, [[Patent Foramen Ovale]])
    • Tetralogy of Fallot with Right to Left Shunt (see Tetralogy of Fallot, [[Tetralogy of Fallot]]): VSD + pulmonary artery stenosis
    • Ventricular Septal Defect (VSD) with Right to Left Shunt (see Ventricular Septal Defect, [[Ventricular Septal Defect]])

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, ARDS, 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: diffusion limitation is absent in normal subjects at rest
  • Etiology
    • Heavy Exercise: due to increased cardiac outut with decreased time available for oxygen diffusion
      • With resulting transient pulmonary interstitial fluid accumulation
      • Effect of Hypoxia: humans will freqently 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, [[Interstitial Lung Disease]]): due to increased cardiac outut with decreased time available for oxygen diffusion combined with thickening of the alveolar capillary membrane

Clinical Manifestations

General Comments

  • Hypoxemia May Be Asymptomatic: in contrast, hypoxia reflects end-organ compromise due to inadequate tissue oxygenation and is always symptomatic (see above)

Cardiovascular Manifestations

Neurologic Manifestations

  • Altered Mentation
  • Anxiety (see Anxiety, [[Anxiety]])
  • Dizziness (see Dizziness, [[Dizziness]])
  • Headache (see Headache, [[Headache]])
  • Increased Intracranial Pressure (see Increased Intracranial Pressure, [[Increased Intracranial Pressure]])
    • Physiology: hypoxemia causes cerebral vasodilation
    • Clinical: potentiation of neurologic injury in traumatic brain injury (TBI), etc
  • Irritability/Restlessness

Pulmonary Manifestations

  • Dyspnea (see Dyspnea, [[Dyspnea]])
  • Pulmonary Vasoconstriction with Worsening of Pulmonary Hypertension (see Pulmonary Hypertension, [[Pulmonary Hypertension]])
    • Physiology: hypoxic pulmonary vasoconstriction is enhanced by acidosis (see Metabolic Acidosis-General, [[Metabolic Acidosis-General]])

Other Manifestations

  • Clubbing (see Clubbing, [[Clubbing]])
    • Epidemiology: may occur with chronic hypoxemia
  • Cyanosis (see Cyanosis, [[Cyanosis]])
  • Polycythemia (see Polycythemia, [[Polycythemia]])

Treatment of Hypoxemia

Oxygen (see Oxygen, [[Oxygen]])

Nasal Cannula (NC)

  • xxx

High-Flow Nasal Cannula (HFNC)

  • Rationale: high-flow nasal cannula appears to decrease dead space [MEDLINE]
  • Contraindications
    • Hypercapnic Respiratory Failure
    • Mid-Maxillary Facial Trauma
    • Suspected Pneumothorax
  • French FLORALI Study Comparing High-Flow Nasal Cannula Oxygen with Standard Oxygen and Non-Invasive Ventilation in Hypoxemic, Non-Hypercapnic Respiratory Failure (NEJM, 2015) [MEDLINE]
    • No Difference in Intubation Rates
    • High-Flow Oxygen Group: improved 90-day mortality
    • High-Flow Oxygen Group: improved ventilator-free days
    • Criticisms of Study
      • Non-invasive ventilation group was unconventionally ventilated with 9 mL/kg PBW, possibly increasing lung injury in this group


  • xxx

Non-Rebreather Mask

  • xxx

Mechanical Ventilation (see General Ventilator Management, [[General Ventilator Management]])

  • xxx


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  • Hypoxemia in acute pulmonary embolism. Chest. 1985;88(6):829-836 [MEDLINE]
  • Mechanism of exercise-induced hypoxemia in horses. Journal of Applied Physiology March 1989 vol. 66 no. 3 1227-1233 [MEDLINE]
  • The contribution of intrapulmonary shunts to the alveolar-to-arterial oxygen difference during exercise is very small. J Physiol 586.9 (2008) pp 2381-2391 [MEDLINE]
  • Intracardiac shunt with hypoxemia caused by right ventricular dysfunction following pericardiocentesis. Can J Cardiol. 2008 September; 24(9): e60-e62 [MEDLINE]
  • Hypoxia and cardiac arrhythmias in breath-hold divers during voluntary immersed breath-holds. Eur J Appl Physiol. 2009 Mar;105(5):673-8. doi: 10.1007/s00421-008-0945-x. Epub 2008 Nov 26 [MEDLINE]
  • Pulmonary vascular and right ventricular dysfunction in adult critical care: current and emerging options for management: a systematic literature review. Crit Care. 2010;14(5):R169 [MEDLINE]
  • Platypnea-orthodeoxia: bilateral lower-lobe pulmonary emboli and review of associated pathophysiology and management. South Med J. 2011 Mar;104(3):215-21. doi: 10.1097/SMJ.0b013e31820bfb54 [MEDLINE]
  • High-flow oxygen administration by nasal cannula for adult and perinatal patients. Respir Care 2013;58:98-122
  • Nasal high-flow versus Venturi mask oxygen therapy after extubation: effects on oxygenation, comfort, and clinical outcome. Am J Respir Crit Care Med 2014;190:282-8
  • Transnasal humidified rapid-insufflation ventilatory exchange (THRIVE): a physiological method of increasing apnoea time in patients with difficult airways. Anaesthesia 2015;70:323-9 [MEDLINE]
  • FLORALI Study. High-flow oxygen through nasal cannula in acute hypoxemic respiratory failure. N Engl J Med. 2015 Jun 4;372(23):2185-96. doi: 10.1056/NEJMoa1503326. Epub 2015 May 17 [MEDLINE]
  • Saving lives with high-flow nasal oxygen. N Engl J Med. 2015 Jun 4;372(23):2225-6. doi: 10.1056/NEJMe1504852. Epub 2015 May 17 [MEDLINE]
  • High-flow nasal cannula oxygen therapy in adults. J Intensive Care. 2015 Mar 31;3(1):15. doi: 10.1186/s40560-015-0084-5. eCollection 2015 [MEDLINE]