Oxygen Transport & Delivery

Quick Answer

Oxygen Transport & Delivery encompasses the physiological mechanisms by which oxygen moves from atmosphere to mitochondria. The oxygen cascade describes the progressive decrease in PO2 from inspired air (160 mmHg) to mitochondria (1-10 mmHg). Haemoglobin is the primary oxygen carrier, with each gram binding 1.34 mL O2 when fully saturated. The sigmoidal oxygen-haemoglobin dissociation curve (P50 = 26.6 mmHg) facilitates both lung loading and tissue unloading through cooperative binding. Oxygen delivery (DO2 = CO x CaO2) normally exceeds consumption (VO2) by 4:1, providing physiological reserve. When DO2 falls below critical threshold (~330 mL/min/m2), oxygen consumption becomes supply-dependent, initiating anaerobic metabolism and lactic acidosis. Monitoring includes SvO2 (normal 65-75%), ScvO2, lactate, and near-infrared spectroscopy (NIRS).

Critical Equations:

• CaO2 = (Hb x 1.34 x SaO2) + (0.003 x PaO2) = approximately 20 mL O2/dL blood
• DO2 = CO x CaO2 x 10 = approximately 1000 mL O2/min (or 500-600 mL/min/m2)
• VO2 = CO x (CaO2 - CvO2) x 10 = approximately 250 mL O2/min (or 110-160 mL/min/m2)
• O2ER = VO2/DO2 = (CaO2 - CvO2)/CaO2 = approximately 25%

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CICM Exam Focus

What Examiners Expect

The CICM First Part examination places significant emphasis on oxygen transport physiology as it underpins critical care interventions. Examiners expect candidates to demonstrate:

Written Examination (SAQ):

• Accurate reproduction of the oxygen cascade with numerical values at each step
• Complete understanding of haemoglobin structure including T and R states
• Ability to draw and annotate the oxygen-haemoglobin dissociation curve with Bohr effect
• Calculation proficiency for CaO2, DO2, VO2, and O2ER using provided data
• Understanding of supply-dependency and critical DO2 concepts
• Clinical application to shock states, anaemia, and hypoxaemia

Viva Examination:

• Systematic explanation of oxygen transport from first principles
• Integration of basic science with clinical scenarios
• Problem-solving for complex cases (e.g., carbon monoxide poisoning, methaemoglobinaemia)
• Discussion of monitoring modalities and their physiological basis
• Evidence-based approach referencing landmark trials (Rivers EGDT, ARISE, ProCESS)

Common SAQ Stems

1. "Describe the oxygen cascade from atmosphere to mitochondria"
2. "Explain the factors affecting the position of the oxygen-haemoglobin dissociation curve"
3. "A patient has Hb 100 g/L, SaO2 98%, PaO2 85 mmHg, CO 5 L/min. Calculate oxygen delivery and consumption"
4. "Discuss the relationship between oxygen delivery and oxygen consumption, including the concept of critical DO2"
5. "Describe the role of 2,3-DPG in oxygen transport and conditions that alter its concentration"

High-Yield Topics

• Oxygen cascade numerical values (must memorise)
• P50 and factors shifting ODC (Bohr effect, 2,3-DPG, temperature, CO)
• Oxygen content equation components and clinical significance
• DO2/VO2 relationship and supply-dependency
• SvO2 physiology and clinical interpretation
• Carbon monoxide and methaemoglobin pathophysiology

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Key Points

1. Oxygen Cascade: Atmospheric PO2 (160 mmHg) progressively decreases through airways (150 mmHg), alveoli (100 mmHg), arterial blood (95-100 mmHg), capillaries (40-50 mmHg), and mitochondria (1-10 mmHg) - this gradient drives diffusion at each step (PMID: 6629910)

2. Haemoglobin Oxygen Binding: Each haemoglobin molecule binds 4 oxygen molecules cooperatively; the Hufner constant is 1.34 mL O2/g Hb (empirically measured, theoretical maximum 1.39 mL/g) (PMID: 393578)

3. Sigmoidal ODC: The S-shaped curve results from cooperative binding (Hill coefficient 2.8) with P50 of 26.6 mmHg at standard conditions (pH 7.4, PaCO2 40 mmHg, 37C) (PMID: 393578)

4. Bohr Effect: Decreased pH and increased CO2 shift the ODC rightward, reducing haemoglobin oxygen affinity and facilitating oxygen unloading in metabolically active tissues (PMID: 5641634)

5. 2,3-DPG Regulation: 2,3-diphosphoglycerate binds deoxyhaemoglobin, stabilising the T-state and reducing oxygen affinity; increases in chronic hypoxia, anaemia, and alkalosis (PMID: 5641634)

6. Normal DO2: Approximately 1000 mL/min or 500-600 mL/min/m2; this represents 4x normal oxygen consumption, providing substantial physiological reserve (PMID: 2193159)

7. Critical DO2: Below approximately 330 mL/min/m2 (or 8-10 mL/kg/min), VO2 becomes supply-dependent with activation of anaerobic metabolism and lactate production (PMID: 2193159)

8. Normal O2ER: Approximately 25% (range 22-32%); maximum extraction 70-80% during exercise or critical illness; extraction ratio inversely correlates with SvO2 (PMID: 11794169)

9. SvO2 Monitoring: Mixed venous oxygen saturation reflects global oxygen supply-demand balance; values less than 65% indicate tissue hypoxia requiring intervention (PMID: 11794169)

10. EGDT Trials Controversy: While Rivers (2001) showed benefit from SvO2-guided resuscitation, later trials (ProCESS, ARISE, ProMISe) found no difference with protocolised care, though all achieved high SvO2 in both arms (PMID: 25295709, 25306775, 25776532)

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Oxygen Cascade

The oxygen cascade describes the progressive decrease in partial pressure of oxygen from atmosphere to mitochondria. This pressure gradient is essential for driving oxygen diffusion at each step of the transport process.

Atmospheric to Inspired Air

Atmospheric oxygen:

• Dry atmospheric pressure at sea level: 760 mmHg (101.3 kPa)
• Oxygen fraction (FiO2): 21% (0.21)
• Atmospheric PO2 = 760 x 0.21 = 160 mmHg (21.3 kPa)
• Nitrogen (78%) and argon (0.9%) comprise remainder (PMID: 6629910)

Humidification effect:

• Air is fully humidified in upper airways to 37C and 100% relative humidity
• Water vapour pressure at 37C: 47 mmHg (6.3 kPa)
• Water vapour dilutes inspired gas, reducing PO2
• Inspired tracheal PO2 = (760 - 47) x 0.21 = 150 mmHg (20 kPa) (PMID: 6629910)

Alveolar Gas

Alveolar gas equation: The alveolar PO2 (PAO2) is calculated using the alveolar gas equation:

PAO2 = FiO2 x (PB - PH2O) - (PaCO2 / R)

Where:

• FiO2 = inspired oxygen fraction (0.21 room air)
• PB = barometric pressure (760 mmHg at sea level)
• PH2O = water vapour pressure (47 mmHg at 37C)
• PaCO2 = arterial CO2 tension (40 mmHg normal)
• R = respiratory quotient (typically 0.8)

Normal alveolar PO2: PAO2 = 0.21 x (760 - 47) - (40 / 0.8) PAO2 = 150 - 50 = 100 mmHg (13.3 kPa) (PMID: 4835221)

Clinical significance:

• Hyperventilation (low PaCO2) increases PAO2
• Hypoventilation (high PaCO2) decreases PAO2
• High altitude (low PB) decreases PAO2
• The alveolar gas equation is essential for calculating A-a gradient

Alveolar-Arterial Gradient

Normal A-a gradient:

• Young healthy adults: 5-15 mmHg (0.7-2 kPa)
• Increases with age: Expected = (Age/4) + 4 mmHg
• Alternative formula: Expected = 2.5 + (0.21 x Age)
• Maximum normal: approximately 25 mmHg in elderly (PMID: 4835221)

Causes of elevated A-a gradient:

Arterial to Capillary

Arterial blood PO2:

• Normal PaO2: 95-100 mmHg (12.7-13.3 kPa)
• The small drop from alveolar (100 mmHg) represents:
  • "Physiological shunt (bronchial, thebesian veins): 2-5% of cardiac output"
  • V/Q mismatch even in normal lungs
  • "Diffusion limitation (minimal in health) (PMID: 13844155)"

Capillary oxygen tension:

• Blood entering capillaries: 95-100 mmHg
• Blood leaving capillaries: 40 mmHg (5.3 kPa) mean
• Oxygen diffuses down concentration gradient into tissues
• Capillary transit time: 0.75-1 second (equilibration normally complete in 0.25 s) (PMID: 13844155)

Tissue and Mitochondrial

Tissue PO2:

• Interstitial PO2: 20-40 mmHg (varies by tissue)
• Cytoplasmic PO2: 5-20 mmHg
• Mitochondrial PO2: 1-10 mmHg (0.1-1.3 kPa)
• Critical mitochondrial PO2: 0.5-1 mmHg (below this, oxidative phosphorylation fails) (PMID: 2193159)

Factors affecting tissue PO2:

• Capillary density (highest in cardiac and skeletal muscle)
• Oxygen consumption rate (highest in brain, heart, kidney)
• Blood flow and DO2
• Haemoglobin concentration and affinity
• Tissue oedema (increases diffusion distance)

Oxygen Cascade Summary Table

High Altitude Physiology

Relevance to Australian/NZ practice:

• Aeromedical retrieval (RFDS, fixed-wing aircraft pressurised to 8000 ft)
• Cabin altitude: 5000-8000 ft (approximately 564-565 mmHg)
• Equivalent FiO2 at 8000 ft: approximately 15.4% (PMID: 6629910)

Compensatory mechanisms:

Critical altitude considerations:

• Unpressurised aircraft: maximum 10,000 ft without supplemental O2
• Patients with respiratory disease: may require supplemental O2 during transport
• ECMO retrieval: specific altitude considerations for oxygenator function

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Haemoglobin Structure

Molecular Structure

Quaternary structure: Haemoglobin is a tetrameric protein with molecular weight of 64,500 Da (64.5 kDa), consisting of:

• Four globin chains: 2 alpha chains (141 amino acids each) + 2 beta chains (146 amino acids each)
• Four haem groups: iron-protoporphyrin IX complexes
• Each subunit binds one oxygen molecule (total 4 O2 per Hb molecule)
• Alpha and beta chains encoded on chromosomes 16 and 11 respectively (PMID: 391134)

Haem group structure:

• Protoporphyrin IX ring with central iron atom
• Iron in ferrous state (Fe2+) binds oxygen reversibly
• Oxidation to ferric state (Fe3+) produces methaemoglobin (cannot bind O2)
• Proximal histidine (F8) links haem to globin chain
• Distal histidine (E7) stabilises oxygen binding (PMID: 391134)

Haemoglobin variants:

T and R States

Tense (T) State - Deoxyhaemoglobin:

• Low oxygen affinity (constrained conformation)
• Salt bridges between alpha1-beta2 and alpha2-beta1 interfaces intact
• 2,3-DPG binding pocket accessible in central cavity
• Preferentially binds H+, CO2, and 2,3-DPG
• Iron atom displaced 0.4 from porphyrin plane (PMID: 391134)

Relaxed (R) State - Oxyhaemoglobin:

• High oxygen affinity (relaxed conformation)
• Salt bridges broken, subunits rotate 15 degrees
• 2,3-DPG binding pocket narrowed (reduced affinity)
• Releases H+ and CO2 (Haldane effect)
• Iron atom moves into porphyrin plane upon O2 binding (PMID: 391134)

Allosteric transition:

• Binding of O2 to one subunit increases affinity of remaining subunits
• T to R transition occurs after 1-2 oxygen molecules bind
• Cooperative binding produces sigmoidal dissociation curve
• Transition enables efficient loading in lungs and unloading in tissues

Cooperative Binding

Hill equation: Y = [O2]^n / (P50^n + [O2]^n)

Where:

• Y = fractional saturation (0 to 1)
• [O2] = oxygen partial pressure
• P50 = partial pressure at 50% saturation
• n = Hill coefficient (cooperativity measure)

Hill coefficient interpretation:

Clinical significance of cooperativity:

• Enables efficient O2 loading in lungs (steep curve at high PO2)
• Facilitates O2 unloading in tissues (steep curve at low PO2)
• Small PO2 changes in tissues cause large O2 release
• Without cooperativity, oxygen delivery would be severely compromised (PMID: 393578)

Myoglobin Comparison

Structure:

• Single polypeptide chain (153 amino acids) with one haem group
• Molecular weight: 17,000 Da
• No allosteric regulation (no cooperative binding)
• Hyperbolic dissociation curve (Hill coefficient = 1)

Functional differences:

Clinical relevance:

• Myoglobin serves as intracellular oxygen reservoir
• High affinity (low P50) facilitates O2 transfer from Hb
• Released during muscle injury (rhabdomyolysis marker)
• Can cause AKI through tubular obstruction and oxidative injury

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Oxygen-Haemoglobin Dissociation Curve

Standard Curve Characteristics

Sigmoidal shape: The oxygen-haemoglobin dissociation curve (ODC) describes the relationship between PO2 and haemoglobin oxygen saturation. The characteristic S-shape results from cooperative binding between haemoglobin subunits.

Key points on the curve:

Clinical implications of curve shape:

• Flat upper portion (PO2 greater than 60 mmHg): Large PO2 changes cause minimal saturation change; provides safety margin for oxygen loading
• Steep middle portion (PO2 20-60 mmHg): Small PO2 changes cause large saturation changes; facilitates tissue oxygen unloading
• Flat lower portion (PO2 less than 20 mmHg): Oxygen bound tightly; reserve for extreme conditions (PMID: 393578)

P50 Definition and Significance

Definition: P50 is the partial pressure of oxygen at which haemoglobin is 50% saturated under standard conditions:

• pH 7.4
• PaCO2 40 mmHg
• Temperature 37C
• Normal 2,3-DPG levels

Normal P50 values:

• Adult HbA: 26.6 mmHg (3.5 kPa) - Severinghaus reference (PMID: 393578)
• Foetal HbF: 19 mmHg (high affinity, left-shifted)
• Myoglobin: 2.8 mmHg (very high affinity)

Clinical interpretation:

Factors Shifting the Curve Rightward

Right shift = decreased oxygen affinity = easier oxygen unloading

1. Decreased pH (Bohr Effect):

• Mechanism: H+ binds to histidine residues, stabilising T-state
• Effect: 0.03-0.05 mmHg increase in P50 per 0.01 pH decrease
• Clinical relevance: Metabolically active tissues (low pH) receive more oxygen
• Evidence: Discovered by Christian Bohr (1904) (PMID: 29043431)

2. Increased PaCO2 (Bohr Effect):

• Mechanism: CO2 forms carbamino compounds with N-terminal amino groups
• Effect: Direct effect on Hb conformation, independent of pH
• Clinical relevance: Tissues producing CO2 receive more oxygen
• The Bohr effect is essential for matching oxygen delivery to metabolic demand (PMID: 29043431)

3. Increased Temperature:

• Mechanism: Thermal effect on protein conformation and O2 binding
• Effect: Approximately 2.4 mmHg increase in P50 per 1C increase
• Clinical relevance: Exercising muscles (elevated temperature) receive more oxygen
• P50 at 40C: approximately 31 mmHg (PMID: 393578)

4. Increased 2,3-DPG:

• Mechanism: 2,3-DPG binds in central cavity between beta chains, stabilising T-state
• Effect: Major regulator of Hb oxygen affinity
• Conditions with increased 2,3-DPG:
  • Chronic hypoxia (altitude, lung disease)
  • Chronic anaemia
  • Alkalosis
  • Hyperthyroidism
  • "Pregnancy (PMID: 5641634)"

Factors Shifting the Curve Leftward

Left shift = increased oxygen affinity = impaired oxygen unloading

1. Increased pH (Bohr Effect):

• Alkalosis increases Hb-O2 affinity
• May cause tissue hypoxia despite normal PaO2 and SaO2
• Clinical scenarios: Hyperventilation, vomiting, diuretic use

2. Decreased PaCO2:

• Hypocapnia shifts curve leftward
• Hyperventilation may worsen tissue oxygenation

3. Decreased Temperature (Hypothermia):

• P50 at 33C: approximately 22 mmHg
• P50 at 30C: approximately 19 mmHg
• Therapeutic hypothermia: Must consider left-shifted curve
• Tissue oxygen extraction may be impaired (PMID: 393578)

4. Decreased 2,3-DPG:

• Conditions with decreased 2,3-DPG:
  • Stored blood (depleted by 2 weeks, regenerates over 24h post-transfusion)
  • Acidosis (decreased synthesis)
  • Hypophosphataemia
  • Septic shock
  • "Hypothyroidism (PMID: 5641634)"

5. Carbon Monoxide (CO):

• Binds haemoglobin with 200-250x affinity of oxygen
• Shifts ODC leftward (Haldane effect)
• Produces cherry-red colour (COHb)
• SpO2 falsely normal (CO absorbs at same wavelength as O2Hb)
• Treatment: 100% O2, hyperbaric oxygen (PMID: 27846906)

6. Methaemoglobin:

• Fe3+ cannot bind oxygen
• Shifts remaining functional Hb leftward
• SpO2 typically reads 85% (saturation gap)
• Causes: Dapsone, nitrates, local anaesthetics, oxidising agents
• Treatment: Methylene blue 1-2 mg/kg IV (PMID: 21532481)

7. Foetal Haemoglobin (HbF):

• P50: 19 mmHg (left-shifted)
• Does not bind 2,3-DPG (gamma chains lack binding site)
• Facilitates O2 transfer from maternal to foetal blood
• Replaced by HbA in first year of life

Bohr Effect in Detail

Discovery: Christian Bohr (1904) demonstrated that CO2 decreases haemoglobin oxygen affinity (PMID: 29043431)

Mechanism:

1. H+ binds to specific amino acid residues (His-146 of beta chain, others)
2. Proton binding stabilises salt bridges in T-state
3. Oxygen affinity decreases (P50 increases)
4. Same mechanism for CO2 (forms carbamino compounds)

Quantitative relationships:

• Bohr coefficient (delta log P50 / delta pH) = -0.48
• For each 0.1 pH decrease, P50 increases by approximately 3 mmHg

Clinical relevance:

• Tissues with high metabolic activity (producing H+ and CO2) receive more oxygen
• Lactic acidosis shifts curve right, potentially improving tissue oxygen delivery
• However, severe acidosis may impair cardiac function, reducing overall DO2

2,3-DPG Physiology

Synthesis and metabolism:

• Produced in erythrocytes via Rapoport-Luebering shunt (glycolysis bypass)
• Concentration: 4-5 mmol/L in RBCs (equimolar with Hb)
• Half-life: approximately 6 hours
• Metabolised by 2,3-DPG phosphatase to 3-phosphoglycerate (PMID: 5641634)

Binding mechanism:

• 2,3-DPG binds in central cavity between two beta chains
• Binding stabilises T-state (deoxyhaemoglobin)
• Reduces oxygen affinity (increases P50)
• One 2,3-DPG molecule per Hb tetramer

Regulation:

Clinical applications:

• Blood storage: 2,3-DPG depleted by day 14; transfused RBCs have high O2 affinity initially
• Massive transfusion: Consider 2,3-DPG depletion effect on O2 delivery
• Regeneration: 2,3-DPG levels normalise within 24 hours post-transfusion (PMID: 5641634)

Carbon Monoxide Poisoning

Pathophysiology:

• CO binds haemoglobin with 200-250 times greater affinity than O2
• Forms carboxyhaemoglobin (COHb)
• Dual mechanism of toxicity:
  1. Reduces oxygen-carrying capacity (COHb cannot carry O2)
  2. Shifts ODC leftward, impairing O2 unloading from remaining oxyHb

Clinical features:

• Headache, confusion, syncope
• Cherry-red skin (rarely seen clinically)
• Cardiac ischaemia (myocardium highly sensitive)
• Delayed neurological sequelae (PMID: 27846906)

Diagnosis:

• COHb level on co-oximetry (not pulse oximetry)
• SpO2 falsely normal (standard pulse oximeter cannot distinguish COHb from O2Hb)
• ABG: Normal or elevated PaO2 with reduced measured SaO2

Management:

• High-flow 100% O2 (reduces CO half-life from 4-6 hours to 60-90 minutes)
• Hyperbaric oxygen (reduces half-life to 15-30 minutes)
• Indications for HBO: Loss of consciousness, neurological symptoms, COHb greater than 25%, pregnancy, cardiac ischaemia (PMID: 27846906)

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Oxygen Content Equation

Complete Equation

Arterial oxygen content (CaO2):

CaO2 = (Hb x 1.34 x SaO2) + (0.003 x PaO2)

Where:

• Hb = haemoglobin concentration (g/dL)
• 1.34 = Hufner constant (mL O2/g Hb)
• SaO2 = arterial oxygen saturation (decimal, 0-1)
• 0.003 = oxygen solubility coefficient (mL O2/dL blood per mmHg PO2)
• PaO2 = arterial oxygen partial pressure (mmHg)

Units:

• CaO2 expressed in mL O2 per dL blood (mL/dL)
• Alternative: mL O2 per 100 mL blood (vol%)

Bound Oxygen Component

Haemoglobin-bound oxygen: CaO2 (bound) = Hb x 1.34 x SaO2

Normal calculation:

• Hb = 15 g/dL
• SaO2 = 0.98 (98%)
• Bound O2 = 15 x 1.34 x 0.98 = 19.7 mL O2/dL

This represents greater than 98% of total oxygen content

Hufner constant:

• Theoretical value: 1.39 mL O2/g Hb (based on molecular weight)
• Empirical value: 1.34 mL O2/g Hb (CICM standard)
• Difference due to: methaemoglobin (1-2%), carboxyhaemoglobin (0.5-1%), measurement variability
• Some references use 1.36 as compromise value (PMID: 393578)

Dissolved Oxygen Component

Dissolved oxygen: CaO2 (dissolved) = 0.003 x PaO2

Normal calculation:

• PaO2 = 100 mmHg
• Dissolved O2 = 0.003 x 100 = 0.3 mL O2/dL

This represents less than 2% of total oxygen content

Solubility coefficient derivation:

• Henry's law: Dissolved gas proportional to partial pressure
• Oxygen solubility in plasma at 37C: 0.003 mL/dL/mmHg
• Extremely low compared to haemoglobin binding
• Becomes significant only at very high PaO2 (hyperbaric oxygen)

Clinical relevance:

• Supplemental O2 has minimal effect on CaO2 once Hb saturated
• Hyperbaric O2 (2-3 ATA): Dissolved O2 can reach 4-6 mL/dL
• At 3 ATA: Dissolved O2 approximately 6 mL/dL (can support life without Hb)

Normal Values and Clinical Calculations

Normal arterial oxygen content:

• Hb = 15 g/dL, SaO2 = 98%, PaO2 = 100 mmHg
• CaO2 = (15 x 1.34 x 0.98) + (0.003 x 100)
• CaO2 = 19.7 + 0.3 = 20 mL O2/dL (PMID: 393578)

Mixed venous oxygen content:

• Hb = 15 g/dL, SvO2 = 75%, PvO2 = 40 mmHg
• CvO2 = (15 x 1.34 x 0.75) + (0.003 x 40)
• CvO2 = 15.1 + 0.12 = 15.2 mL O2/dL

Arteriovenous oxygen difference:

• Ca-vO2 = CaO2 - CvO2 = 20 - 15.2 = 4.8 mL O2/dL (normal 4-6 mL/dL)

Clinical Scenarios

Scenario 1: Severe Anaemia

• Hb = 7 g/dL, SaO2 = 100%, PaO2 = 100 mmHg
• CaO2 = (7 x 1.34 x 1.0) + (0.003 x 100) = 9.4 + 0.3 = 9.7 mL O2/dL
• Oxygen content reduced by 50% despite normal saturation
• Demonstrates importance of Hb for oxygen transport

Scenario 2: Hypoxaemia

• Hb = 15 g/dL, SaO2 = 85%, PaO2 = 55 mmHg
• CaO2 = (15 x 1.34 x 0.85) + (0.003 x 55) = 17.1 + 0.17 = 17.3 mL O2/dL
• 15% reduction in CaO2 with significant hypoxaemia

Scenario 3: Carbon Monoxide Poisoning

• Hb = 15 g/dL, COHb = 40%, SaO2 (functional) = 100%
• Functional Hb = 15 x 0.6 = 9 g/dL
• CaO2 = (9 x 1.34 x 1.0) + (0.003 x PaO2) = 12 mL O2/dL
• SpO2 may read 100% but true oxygen content severely reduced

Scenario 4: Polycythaemia

• Hb = 20 g/dL, SaO2 = 98%, PaO2 = 100 mmHg
• CaO2 = (20 x 1.34 x 0.98) + (0.003 x 100) = 26.3 + 0.3 = 26.6 mL O2/dL
• Increased oxygen content, but viscosity may impair DO2

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Oxygen Delivery (DO2)

DO2 Equation

Definition: DO2 = Cardiac Output x Arterial Oxygen Content

Complete equation: DO2 = CO x CaO2 x 10

Where:

• CO = cardiac output (L/min)
• CaO2 = arterial oxygen content (mL O2/dL)
• 10 = conversion factor (dL to L)

Alternative expression: DO2 = CO x [(Hb x 1.34 x SaO2) + (0.003 x PaO2)] x 10

Normal Values

Absolute DO2:

• CO = 5 L/min, CaO2 = 20 mL O2/dL
• DO2 = 5 x 20 x 10 = 1000 mL O2/min
• Range: 800-1200 mL O2/min (PMID: 2193159)

Indexed DO2 (DO2I):

• Indexed to body surface area (BSA)
• Normal BSA: 1.7-2.0 m2
• DO2I = DO2 / BSA = 500-600 mL/min/m2
• Range: 450-650 mL/min/m2

Alternative indexing:

• By body weight: 10-15 mL/kg/min
• Allows comparison across different patient populations

Determinants of DO2

Cardiac output components:

• Heart rate (normal 60-100 bpm)
• Stroke volume (normal 60-100 mL)
• CO = HR x SV (PMID: 11794169)

Stroke volume determinants:

Oxygen content determinants:

Critical DO2

Definition: Critical DO2 is the threshold below which oxygen consumption becomes supply-dependent and anaerobic metabolism begins.

Normal value:

• Critical DO2: approximately 330 mL/min/m2 (8-10 mL/kg/min)
• Critical DO2I: 8-10 mL/min/m2
• Represents approximately 50-60% of normal DO2 (PMID: 2193159)

Evidence base:

• Vincent et al. (1990) defined biphasic DO2-VO2 relationship (PMID: 2193159)
• Below critical DO2, VO2 decreases linearly with DO2
• Lactate production begins as anaerobic metabolism activated

Factors affecting critical DO2:

Clinical significance:

• Goal: Maintain DO2 greater than 2x critical threshold
• Traditional target: DO2I greater than 600 mL/min/m2
• "Goal-directed therapy" aims to achieve supranormal DO2
• Modern evidence: Supranormal DO2 targets not beneficial (PMID: 25295709)

Clinical Applications

Shock states:

Optimisation strategies:

1. Increase CO: Fluids, inotropes, reduce afterload
2. Increase Hb: Transfusion (target variable by context)
3. Increase SaO2: Oxygen therapy, ventilation support
4. Reduce VO2: Treat fever, sedate, mechanical ventilation

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Oxygen Consumption (VO2)

VO2 Equation

Fick principle derivation: VO2 = CO x (CaO2 - CvO2) x 10

Where:

• CO = cardiac output (L/min)
• CaO2 = arterial oxygen content (mL O2/dL)
• CvO2 = mixed venous oxygen content (mL O2/dL)
• 10 = conversion factor

Alternative expression: VO2 = CO x [(Hb x 1.34) x (SaO2 - SvO2)] x 10

Normal Values

Absolute VO2:

• CO = 5 L/min, CaO2 = 20 mL/dL, CvO2 = 15 mL/dL
• VO2 = 5 x (20 - 15) x 10 = 250 mL O2/min
• Range: 200-300 mL O2/min at rest (PMID: 2193159)

Indexed VO2 (VO2I):

• VO2I = VO2 / BSA
• Normal: 110-160 mL/min/m2
• Alternative: 3-4 mL/kg/min

Factors affecting VO2:

Fick Principle

Historical context: Adolf Fick (1870) proposed that oxygen consumption equals the product of blood flow and arteriovenous oxygen difference.

Equation rearrangement:

• VO2 = CO x (CaO2 - CvO2) [Fick equation for VO2]
• CO = VO2 / (CaO2 - CvO2) [Fick equation for cardiac output]

Requirements for measurement:

1. Mixed venous blood sample (pulmonary artery catheter)
2. Arterial blood sample
3. Either measured VO2 (metabolic cart) or assumed value

Assumed VO2 values:

• 3-4 mL/kg/min (resting, sedated patient)
• 125 mL/min/m2 (LaFarge and Miettinen constants)
• Limitations: Assumed VO2 may not reflect actual metabolic state

Clinical applications:

• Cardiac output calculation from PA catheter data
• Shunt fraction calculation
• Assessment of tissue oxygen extraction (PMID: 6629910)

Factors Affecting VO2

Increased VO2:

Decreased VO2:

Lactate Production

Anaerobic threshold:

• When DO2 falls below critical DO2, VO2 becomes supply-dependent
• Cells switch to anaerobic glycolysis for ATP production
• Lactate accumulates as pyruvate cannot enter Krebs cycle
• Normal lactate: less than 2 mmol/L (PMID: 23194469)

Lactate kinetics:

• Production: 1-1.5 mmol/kg/hour normally
• Clearance: Primarily hepatic (60%), also renal (30%)
• Half-life: 15-20 minutes with normal clearance
• Elevated in: Shock, hypoxia, liver failure, mitochondrial dysfunction

Clinical significance:

• Lactate greater than 2 mmol/L: Tissue hypoperfusion likely
• Lactate greater than 4 mmol/L: Associated with increased mortality
• Lactate clearance: Prognostic marker in sepsis (20% clearance in 6h associated with improved survival) (PMID: 23194469)

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Oxygen Extraction Ratio

O2ER Equation

Definition: O2ER = VO2 / DO2

Alternative expression: O2ER = (CaO2 - CvO2) / CaO2

Simplified form: O2ER = (SaO2 - SvO2) / SaO2

Normal Values

Normal O2ER:

• O2ER = VO2 / DO2 = 250 / 1000 = 0.25 (25%)
• Normal range: 22-32%
• Maximum: 70-80% (exercise, critical illness)

Interpretation:

Relationship to SvO2

Mathematical relationship:

• SvO2 = SaO2 x (1 - O2ER)
• If SaO2 = 100% and O2ER = 25%, then SvO2 = 75%
• SvO2 inversely correlates with O2ER

Clinical correlation:

Critical Extraction

Maximum extraction capacity:

• Healthy tissues: O2ER max approximately 70-80%
• Limited by: Capillary transit time, diffusion distance, mitochondrial function
• Beyond critical O2ER: Anaerobic metabolism ensues

Sepsis extraction defect:

• Septic patients may fail to increase extraction appropriately
• Mitochondrial dysfunction limits O2 utilisation
• "Cytopathic hypoxia": Cells cannot use available oxygen
• May see normal/high SvO2 despite tissue hypoxia (PMID: 11794169)

Clinical implications:

• Low SvO2: Increase DO2 (fluids, inotropes, transfusion)
• High SvO2 with elevated lactate: Consider sepsis, extraction defect
• Monitor lactate clearance as tissue oxygenation marker

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Supply Dependency

Biphasic DO2-VO2 Relationship

Normal physiology: The relationship between oxygen delivery (DO2) and consumption (VO2) demonstrates two distinct phases:

Supply-independent phase (DO2 greater than critical DO2):

• VO2 remains constant despite changes in DO2
• Tissues extract more/less oxygen to maintain VO2
• O2ER varies inversely with DO2
• Represents physiological reserve

Supply-dependent phase (DO2 less than critical DO2):

• VO2 becomes linearly dependent on DO2
• Maximum extraction reached (O2ER greater than 70%)
• Any further DO2 reduction causes proportional VO2 reduction
• Anaerobic metabolism begins (PMID: 2193159)

Anaerobic Threshold

Definition: The point at which oxygen delivery becomes insufficient to meet metabolic demands, triggering anaerobic metabolism.

Identification:

• Critical DO2: approximately 330 mL/min/m2
• Critical O2ER: approximately 70%
• Lactate begins to rise
• Base deficit increases

Cellular consequences:

1. ATP production falls (2 ATP/glucose vs 36 ATP aerobically)
2. Lactate accumulates
3. Intracellular acidosis
4. Ion pump failure
5. Cell swelling and death

Clinical detection:

Pathological Supply Dependency

Concept: Some critically ill patients exhibit supply dependency at higher-than-normal DO2 levels.

Proposed mechanisms:

1. Microcirculatory dysfunction: Maldistribution of flow
2. Mitochondrial dysfunction: Impaired O2 utilisation
3. Increased metabolic demand: Higher critical DO2
4. Mathematical coupling: Measurement artefact (shared variables)

Sepsis paradigm:

• Early goal-directed therapy targeted supranormal DO2
• Rivers trial (2001) showed benefit of SvO2-guided resuscitation (PMID: 11794169)
• Later trials (ProCESS, ARISE, ProMISe) showed usual care equally effective
• Current understanding: Achieving normal SvO2 important, supranormal targets not beneficial (PMID: 25295709, 25306775, 25776532)

Evidence: EGDT Trials

Rivers et al. (2001) - Original EGDT (PMID: 11794169):

• Single-centre RCT, N = 263
• SvO2-targeted protocol vs standard care
• Mortality: 30.5% vs 46.5% (ARR 16%)
• Established SvO2 greater than 70% as resuscitation target

ProCESS Trial (2014) - NEJM (PMID: 25295709):

• Multicentre RCT, N = 1341
• Protocol-based EGDT vs protocol-based standard care vs usual care
• No mortality difference (21.0% vs 18.2% vs 18.9%)
• Usual care had improved since Rivers era

ARISE Trial (2014) - NEJM (PMID: 25306775):

• Multicentre RCT (Australian), N = 1600
• EGDT vs usual care
• No mortality difference (18.6% vs 18.8%)
• Australian practice already included aggressive early resuscitation

ProMISe Trial (2015) - NEJM (PMID: 25776532):

• Multicentre RCT (UK), N = 1260
• EGDT vs usual care
• No mortality difference (29.5% vs 29.2%)
• Confirmed findings of ProCESS and ARISE

Meta-analysis (2017) - JAMA (PMID: 28052460):

• Individual patient data from ProCESS, ARISE, ProMISe (N = 3723)
• No benefit of EGDT vs usual care
• Mortality: 24.9% vs 25.4% (RR 0.97, 95% CI 0.82-1.14)

Current interpretation:

• Early recognition and resuscitation are key
• SvO2 targeting may be beneficial but formal protocol not required
• Usual care in modern ICUs achieves similar endpoints
• Focus on timely antibiotics, source control, appropriate fluid resuscitation

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Tissue Oxygenation

Diffusion

Fick's law of diffusion: The rate of gas diffusion is proportional to:

• Surface area
• Concentration gradient
• Diffusion coefficient (gas solubility / square root molecular weight)
• Inversely proportional to diffusion distance

Oxygen diffusion:

• From capillary to mitochondria across 20-100 micrometres
• Driven by PO2 gradient (40 mmHg capillary to 1-10 mmHg mitochondria)
• Limited by: Tissue oedema, increased diffusion distance, reduced capillary density

Krogh cylinder model:

• Describes oxygen diffusion from single capillary to surrounding tissue
• Defines "lethal corner"
• tissue area farthest from two adjacent capillaries
• Oxygen tension lowest at these corners, first to become hypoxic
• Capillary recruitment during exercise increases tissue coverage

Capillary Density

Normal capillary density:

Capillary recruitment:

• At rest, only 25% of capillaries perfused
• Exercise/hypoxia: Recruitment of previously closed capillaries
• Reduces diffusion distance, increases surface area
• Mediated by local metabolites (adenosine, K+, H+, CO2)

Critical illness effects:

• Microcirculatory dysfunction: Heterogeneous capillary perfusion
• "Stopped flow" capillaries adjacent to "flowing" capillaries
• Increases diffusion distance for some tissue regions
• May explain tissue hypoxia despite adequate global DO2

Mitochondrial Function

Oxidative phosphorylation:

• Final step in oxygen cascade
• Cytochrome c oxidase (Complex IV) binds O2
• Requires PO2 greater than 0.5-1 mmHg for function
• Produces 34-36 ATP per glucose molecule via electron transport chain

Critical mitochondrial PO2:

• Minimum: 0.5-1 mmHg
• Optimal: 1-10 mmHg
• Above 10 mmHg: No additional benefit
• Cells can function at very low PO2 if delivery is maintained

Mitochondrial dysfunction in critical illness:

• Sepsis: Inflammatory mediators (NO, peroxynitrite) damage complexes
• Ischaemia-reperfusion: Oxidative stress, calcium overload
• Drugs: Propofol (PRIS), metformin (lactic acidosis)
• Histotoxic hypoxia: Cyanide (blocks Complex IV)

Cytopathic hypoxia:

• Cells cannot utilise available oxygen
• Mitochondrial dysfunction despite adequate DO2
• SvO2 may be normal or high
• Lactate elevated due to impaired oxidative phosphorylation
• Seen in severe sepsis, post-cardiac arrest (PMID: 11794169)

Tissue Oxygen Monitoring

Near-infrared spectroscopy (NIRS):

• Non-invasive monitoring of tissue oxygen saturation (StO2)
• Wavelengths 700-900 nm penetrate tissue
• Measures oxyhaemoglobin:deoxyhaemoglobin ratio
• Normal StO2: 75-85%
• Reflects tissue venous saturation (predominantly)
• Applications: Cerebral oximetry, muscle StO2 in shock (PMID: 17378905)

Tissue PO2 monitoring:

• Direct measurement via implanted electrodes
• Used in traumatic brain injury (PbtO2)
• Normal brain PO2: 25-35 mmHg
• Ischaemic threshold: less than 15-20 mmHg
• Target in TBI: greater than 20 mmHg

Sublingual capnometry:

• Measures mucosal CO2 (reflects perfusion)
• Elevated in shock states
• May predict outcomes in resuscitation

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Clinical Applications

Shock States

Hypovolaemic Shock:

Management: Fluid resuscitation, blood transfusion if haemorrhage

Cardiogenic Shock:

Management: Inotropes, mechanical support (IABP, ECMO), treat underlying cause

Distributive Shock (Sepsis):

Note: High SvO2 with elevated lactate suggests extraction defect/mitochondrial dysfunction

Management: Fluids, vasopressors, antibiotics, source control (PMID: 11794169)

Obstructive Shock:

• Massive PE, cardiac tamponade, tension pneumothorax
• CO markedly reduced due to mechanical obstruction
• Management: Treat underlying cause urgently

Anaemia

Oxygen transport in anaemia:

• CaO2 reduced proportionally to Hb reduction
• Compensatory mechanisms:
  • Increased CO (hyperdynamic circulation)
  • Increased O2ER
  • Rightward shift of ODC (increased 2,3-DPG)
  • Reduced blood viscosity (improved flow)

Transfusion triggers:

TRICC Trial (1999) (PMID: 9971864):

• Restrictive (Hb 70-90 g/L) vs liberal (Hb 100-120 g/L) transfusion
• No mortality difference (restrictive may be superior in some subgroups)
• Established restrictive transfusion as standard practice

High-Output States

Conditions:

• Sepsis, thyrotoxicosis, burns, pregnancy, AV fistula
• Characterised by elevated CO and DO2

Oxygen transport implications:

• DO2 increased but VO2 also increased
• O2ER may be normal or low
• SvO2 often elevated
• Tissue hypoxia may still occur if VO2 exceeds capacity

Thyroid Storm:

• VO2 increased 50-100%
• High CO, high DO2
• Treatment: Beta-blockade, anti-thyroid drugs, supportive care

Burns:

• Hypermetabolic state, VO2 increased 50-100%
• Fluid requirements markedly increased
• Ensure adequate DO2 through resuscitation

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Monitoring

Mixed Venous Oxygen Saturation (SvO2)

Definition and measurement:

• Oxygen saturation of blood in pulmonary artery
• Requires pulmonary artery catheter
• Continuous monitoring via fibreoptic oximetry available

Normal values:

• Normal SvO2: 65-75%
• Reflects global oxygen supply-demand balance

Interpretation:

Limitations:

• Requires PA catheter (invasive)
• Does not detect regional hypoxia
• May be misleadingly high in sepsis (extraction defect)
• Not superior to ScvO2 for routine monitoring

Central Venous Oxygen Saturation (ScvO2)

Definition:

• Oxygen saturation of blood in superior vena cava
• Measured via central venous catheter tip
• Less invasive than SvO2

Comparison to SvO2:

• ScvO2 typically 5-10% higher than SvO2
• Reflects upper body oxygen extraction only
• Excludes coronary sinus and lower body drainage
• May be used as SvO2 surrogate (PMID: 11794169)

Clinical utility:

• Rivers EGDT targeted ScvO2 greater than 70%
• Simpler to obtain than SvO2
• Adequate for resuscitation guidance
• Limitations: Does not detect lower body hypoxia

Lactate

Production and clearance:

• Normal production: 1-1.5 mmol/kg/hour
• Clearance: Hepatic (60%), renal (30%)
• Normal level: less than 2 mmol/L
• Half-life: 15-20 minutes with normal clearance

Types of lactic acidosis:

Clinical interpretation:

• Lactate greater than 2 mmol/L: Abnormal, investigate cause
• Lactate greater than 4 mmol/L: High mortality, aggressive resuscitation
• Lactate clearance: greater than 10-20% in 2-6 hours indicates response to treatment
• Persistent elevation: Consider ongoing hypoperfusion or Type B cause (PMID: 23194469)

Sepsis-3 criteria:

• Septic shock: Sepsis + vasopressors required + lactate greater than 2 mmol/L despite adequate fluid resuscitation
• Lactate as prognostic marker in sepsis

Near-Infrared Spectroscopy (NIRS)

Principles:

• Near-infrared light (700-900 nm) penetrates tissue
• Oxyhaemoglobin and deoxyhaemoglobin have different absorption spectra
• Calculates tissue oxygen saturation (StO2)
• Primarily reflects venous saturation (capillary blood 70-80% venous)

Applications:

Cerebral NIRS:

• Monitors regional cerebral oxygenation
• Desaturation during cardiac surgery predicts neurological injury
• Useful during cardiac arrest (prognostication)
• Limitations: Contamination by extracranial tissue, inability to distinguish cause

Muscle StO2 in shock:

• Thenar eminence commonly used site
• Decreased in haemorrhagic and cardiogenic shock
• Responds to resuscitation
• May guide transfusion and fluid therapy (PMID: 17378905)

Tissue Oxygen Tension

Brain tissue oxygen (PbtO2):

• Measured via intraparenchymal probe
• Normal: 25-35 mmHg
• Ischaemic threshold: less than 15-20 mmHg
• Target in TBI: greater than 20 mmHg

Clinical use in TBI:

• Combined with ICP monitoring
• Guides CPP augmentation, transfusion, FiO2
• Low PbtO2 associated with worse outcomes
• Intervention to increase PbtO2 may improve outcomes (PMID: 22024899)

Gastric Tonometry

Historical context:

• Measures gastric mucosal PCO2
• Splanchnic perfusion marker
• Elevated pCO2 indicates ischaemia
• Superseded by other monitoring modalities

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Australian and New Zealand Context

Indigenous Health Considerations

Aboriginal and Torres Strait Islander populations:

• Higher prevalence of anaemia (10-15% vs 5% non-Indigenous)
• Chronic kidney disease more common (CKD-associated anaemia)
• Rheumatic heart disease (high-output cardiac failure)
• Remote location: Delayed access to ICU care
• Cultural considerations: Family involvement in decision-making
• Aboriginal Health Workers (AHWs) and Aboriginal Liaison Officers (ALOs) as essential team members (PMID: 25406584)

Specific challenges:

• Chronic anaemia may be well-tolerated (compensation)
• Transfusion triggers may differ from standard recommendations
• Communication through interpreters and AHWs
• Respect for Sorry Business and cultural protocols

Māori health (New Zealand):

• Similar disparities in chronic disease burden
• Whānau-centered decision-making
• Tikanga (cultural practices) should inform care
• Higher rates of diabetes, cardiovascular disease

ANZICS CORE Data

Relevance to oxygen delivery:

• ANZICS Clinical Outcomes and Resource Evaluation (CORE)
• Australian and New Zealand adult intensive care database
• Provides local epidemiology for benchmarking
• Studies on transfusion practices, resuscitation endpoints (PMID: 25306775)

Transfusion in ANZ ICUs:

• TRANSFUSE study (Australian-led): Transfusion of fresher vs older blood
• No difference in 90-day mortality
• Confirms age of blood not critical factor
• Restrictive transfusion generally practiced (PMID: 26492988)

Retrieval Medicine

Aeromedical considerations:

• Cabin altitude affects oxygen cascade
• Decreased PIO2 at altitude requires supplemental O2
• RFDS and state retrieval services manage remote patients
• ECMO retrieval: Specific considerations for oxygenator function

Practical implications:

• Ensure adequate FiO2 for altitude during transport
• Consider Hb optimisation before transport
• Monitor SpO2 continuously during flight
• Pressurised aircraft (RFDS): Cabin altitude 5000-8000 ft

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SAQ Practice Questions

SAQ 1: Oxygen Cascade and Delivery Calculation

Question (15 marks, 25 minutes):

A 65-year-old man is admitted to ICU following major abdominal surgery. He is mechanically ventilated on FiO2 0.40. His blood gas shows: pH 7.32, PaCO2 35 mmHg, PaO2 85 mmHg, HCO3 18 mmol/L, lactate 4.2 mmol/L. Haemoglobin is 95 g/L. Cardiac output (thermodilution) is 6.5 L/min. SvO2 is 58%.

a) Calculate this patient's arterial oxygen content (CaO2). Show your working. (3 marks)

b) Calculate this patient's oxygen delivery (DO2) and compare it to normal. (3 marks)

c) Calculate this patient's oxygen consumption (VO2) and oxygen extraction ratio (O2ER). (4 marks)

d) Interpret the elevated lactate in the context of your calculated oxygen transport parameters. (3 marks)

e) Outline your management priorities to optimise oxygen delivery to tissues. (2 marks)

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Model Answer:

a) Arterial oxygen content calculation (3 marks)

Using the oxygen content equation: CaO2 = (Hb x 1.34 x SaO2) + (0.003 x PaO2)

First, calculate SaO2 from PaO2 using ODC (or assume from clinical context):

• PaO2 85 mmHg = SaO2 approximately 96% (from ODC)

CaO2 = (9.5 g/dL x 1.34 x 0.96) + (0.003 x 85) CaO2 = 12.2 + 0.26 CaO2 = 12.5 mL O2/dL

(Note: Hb 95 g/L = 9.5 g/dL for calculation)

Normal CaO2: 18-20 mL O2/dL - this patient is significantly reduced due to anaemia

b) Oxygen delivery calculation (3 marks)

DO2 = CO x CaO2 x 10

DO2 = 6.5 L/min x 12.5 mL/dL x 10 DO2 = 812.5 mL O2/min

Or indexed: DO2I = 812.5 / 1.9 (assumed BSA) = 428 mL/min/m2

Normal DO2: 1000 mL/min (500-600 mL/min/m2) This patient's DO2 is approximately 80% of normal despite elevated CO

c) Oxygen consumption and extraction ratio (4 marks)

CvO2 calculation: CvO2 = (Hb x 1.34 x SvO2) + (0.003 x PvO2)

• Assume PvO2 approximately 30 mmHg (from SvO2 58%) CvO2 = (9.5 x 1.34 x 0.58) + (0.003 x 30) CvO2 = 7.4 + 0.09 CvO2 = 7.5 mL O2/dL

VO2 calculation: VO2 = CO x (CaO2 - CvO2) x 10 VO2 = 6.5 x (12.5 - 7.5) x 10 VO2 = 325 mL O2/min

O2ER calculation: O2ER = VO2 / DO2 = 325 / 812.5 O2ER = 0.40 (40%)

Alternative: O2ER = (CaO2 - CvO2) / CaO2 = (12.5 - 7.5) / 12.5 = 0.40

Normal O2ER: 22-32% - this patient has increased extraction indicating DO2-VO2 mismatch

d) Lactate interpretation (3 marks)

The elevated lactate (4.2 mmol/L) indicates tissue hypoxia despite:

• Compensatory increased CO: 6.5 L/min (above normal 5 L/min)
• Increased O2ER: 40% (above normal 25%)

Key findings:

1. Reduced CaO2 due to anaemia (Hb 95 g/L) is the primary limiting factor
2. SvO2 58% indicates increased tissue oxygen extraction approaching critical threshold
3. O2ER 40% is elevated but has not reached maximum (70-80%)
4. DO2 approximately 430 mL/min/m2 is approaching critical DO2 (330 mL/min/m2)

The lactate elevation suggests the patient is on the descending limb of the DO2-VO2 curve, with regional or global oxygen debt accumulating. The metabolic acidosis (pH 7.32, HCO3 18) supports anaerobic metabolism.

e) Management priorities (2 marks)

1. Increase CaO2:

   • Blood transfusion to Hb 80-90 g/L (increases CaO2 by 20-30%)
   • Increase FiO2 if required (limited benefit as SaO2 already 96%)

2. Maintain/augment CO:

   • Ensure adequate preload (fluid bolus if responsive)
   • Inotropic support if preload optimised and SV remains low

3. Reduce VO2:

   • Ensure adequate sedation
   • Treat fever if present
   • Optimise ventilator settings to reduce work of breathing

4. Address underlying cause:

   • Investigate for surgical complication (bleeding, sepsis)
   • Lactate source identification
   • Serial lactate monitoring for clearance

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SAQ 2: Oxygen-Haemoglobin Dissociation Curve

Question (15 marks, 25 minutes):

a) Draw and label the oxygen-haemoglobin dissociation curve, indicating P50 and the significance of its shape. (4 marks)

b) Explain the Bohr effect and its physiological significance. (3 marks)

c) Describe the role of 2,3-DPG in oxygen transport and list four conditions that alter its concentration. (4 marks)

d) A patient with carbon monoxide poisoning has SpO2 reading of 99% but is confused and has a lactate of 8 mmol/L. Explain the pathophysiology of this clinical picture. (4 marks)

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Model Answer:

a) Oxygen-haemoglobin dissociation curve (4 marks)

[Description of curve that would be drawn]

Key features to include:

• Axes: X-axis = PO2 (mmHg), Y-axis = Oxygen saturation (%)
• Sigmoidal (S-shaped) curve with steep middle section
• P50 marked at 26.6 mmHg (50% saturation)
• Key points:
  • PO2 100 mmHg = 97-98% saturation (arterial, flat portion)
  • PO2 40 mmHg = 75% saturation (mixed venous)
  • PO2 60 mmHg = 90% saturation (steep portion begins)

Significance of sigmoid shape:

1. Flat upper portion: Large PO2 changes (100 to 60 mmHg) cause minimal saturation change - provides safety margin for oxygen loading in lungs
2. Steep middle portion: Small PO2 changes (60 to 20 mmHg) cause large saturation changes - facilitates oxygen unloading in metabolically active tissues
3. Results from cooperative binding between haemoglobin subunits (Hill coefficient 2.8)

b) Bohr effect explanation (3 marks)

Definition: The decrease in haemoglobin oxygen affinity caused by decreased pH and increased CO2.

Mechanism:

• H+ ions bind to histidine residues on haemoglobin (particularly His-146 on beta chains)
• This binding stabilises the T-state (deoxyhaemoglobin)
• Reduces oxygen affinity, shifting ODC to the right
• CO2 also forms carbamino compounds with terminal amino groups, independently reducing affinity

Quantification: Bohr coefficient = -0.48 (delta log P50 / delta pH)

Physiological significance:

1. Tissue level: Metabolically active tissues produce H+ and CO2, causing local right-shift of ODC
2. Result: More oxygen is released to tissues with highest metabolic demand
3. Pulmonary level: As CO2 is eliminated and pH rises, ODC shifts left, enhancing oxygen loading
4. Elegant matching: Automatically couples oxygen delivery to metabolic demand without central control

c) 2,3-DPG role and regulation (4 marks)

Role in oxygen transport:

• 2,3-diphosphoglycerate (2,3-DPG) is an allosteric modulator of haemoglobin
• Binds in central cavity between two beta chains of deoxyhaemoglobin
• Stabilises T-state (low O2 affinity)
• Reduces oxygen affinity, facilitating tissue oxygen unloading
• Effect: Right shift of ODC, increased P50

Concentration: 4-5 mmol/L in erythrocytes (equimolar with Hb)

Conditions that ALTER 2,3-DPG:

Clinical significance of stored blood:

• Fresh blood: Normal 2,3-DPG and oxygen delivery
• Stored blood (greater than 2 weeks): Depleted 2,3-DPG, left-shifted curve
• Transfused RBCs regenerate 2,3-DPG within 24 hours
• Massive transfusion may temporarily impair tissue oxygen unloading

d) Carbon monoxide poisoning pathophysiology (4 marks)

Clinical picture explanation: The patient has SpO2 99% but is symptomatic (confusion) with elevated lactate (8 mmol/L) - this apparent paradox is explained by CO pathophysiology:

Mechanism 1 - Reduced oxygen-carrying capacity:

• CO binds haemoglobin with 200-250x greater affinity than O2
• Forms carboxyhaemoglobin (COHb) which cannot carry oxygen
• Reduces functional haemoglobin concentration
• CaO2 = (Functional Hb x 1.34 x SaO2) + dissolved O2 is significantly reduced

Mechanism 2 - Left shift of ODC:

• CO binding to one subunit increases O2 affinity of remaining subunits (Haldane effect)
• Shifts ODC to the left
• Impairs oxygen unloading at tissue level
• Tissues receive less oxygen even from functional oxyhaemoglobin

Mechanism 3 - Pulse oximetry limitation:

• Standard pulse oximeters use two wavelengths (660 nm and 940 nm)
• COHb absorbs light similarly to O2Hb at 660 nm
• SpO2 therefore reads falsely normal/high
• Co-oximetry (4+ wavelengths) required to detect COHb

Clinical consequences:

1. Tissue hypoxia despite apparent normal SpO2
2. Cellular dysfunction: Brain and heart most vulnerable (high O2 demand)
3. Anaerobic metabolism: Lactate production from oxygen debt
4. Symptoms: Confusion represents cerebral hypoxia

Diagnosis: Requires co-oximetry showing elevated COHb level

Treatment:

• 100% O2 (reduces COHb half-life from 4-6 hours to 60-90 minutes)
• Hyperbaric oxygen for severe cases (half-life 15-30 minutes)

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Viva Scenarios

Viva 1: Oxygen Transport and Clinical Application

Scenario: You are the ICU registrar reviewing a 55-year-old woman with septic shock secondary to cholangitis. She has been resuscitated with 3L crystalloid. Her observations show HR 110, BP 85/50 (MAP 62), and she is on noradrenaline 0.15 mcg/kg/min. Central venous catheter in situ with ScvO2 48%. Lactate 5.8 mmol/L. Hb 85 g/L.

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Examiner: Tell me about the oxygen cascade from atmosphere to tissues.

Candidate: The oxygen cascade describes the progressive decrease in partial pressure of oxygen from inspired air to mitochondria. This gradient drives oxygen diffusion at each step.

Starting at the atmosphere, PO2 is 160 mmHg at sea level (760 mmHg x 21%). After humidification in the upper airways, tracheal PO2 drops to 150 mmHg due to water vapour pressure of 47 mmHg. In the alveolus, PO2 is further reduced to approximately 100 mmHg due to CO2 dilution, calculated by the alveolar gas equation.

Arterial blood PO2 is 95-100 mmHg, slightly lower than alveolar due to physiological shunt and V/Q mismatch. Mixed venous blood returning to the heart has PO2 of approximately 40 mmHg, representing the extraction by tissues. At the tissue level, interstitial PO2 is 20-40 mmHg, and mitochondrial PO2 is just 1-10 mmHg, which is sufficient for oxidative phosphorylation.

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Examiner: This patient has ScvO2 of 48%. What does this tell you?

Candidate: A ScvO2 of 48% is critically low and indicates a significant mismatch between oxygen delivery and consumption. Normal ScvO2 is 65-75%, reflecting approximately 25% oxygen extraction.

Low ScvO2 indicates that tissues are extracting a very high proportion of delivered oxygen to meet metabolic demands. Using the relationship O2ER = (SaO2 - SvO2)/SaO2, if we assume SaO2 of 98%, then O2ER is approximately 51%, which is markedly elevated.

The causes of low ScvO2 fall into two categories:

1. Reduced DO2: Low cardiac output, anaemia (Hb 85 g/L in this case), hypoxaemia
2. Increased VO2: Sepsis, fever, shivering, work of breathing

In this patient with septic shock, the low ScvO2 likely reflects inadequate cardiac output despite initial resuscitation, compounded by anaemia reducing oxygen-carrying capacity, while sepsis is driving increased oxygen consumption.

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Examiner: Calculate this patient's oxygen delivery assuming cardiac output is 4 L/min.

Candidate: To calculate DO2, I need to first calculate CaO2.

CaO2 = (Hb x 1.34 x SaO2) + (0.003 x PaO2)

Assuming Hb 85 g/L = 8.5 g/dL, SaO2 98%, and PaO2 100 mmHg:

CaO2 = (8.5 x 1.34 x 0.98) + (0.003 x 100) CaO2 = 11.2 + 0.3 = 11.5 mL O2/dL

DO2 = CO x CaO2 x 10 DO2 = 4 x 11.5 x 10 = 460 mL O2/min

Indexed to BSA of approximately 1.7 m2: DO2I = 460/1.7 = 270 mL/min/m2

This is markedly reduced. Normal DO2I is 500-600 mL/min/m2, and critical DO2I is approximately 330 mL/min/m2. This patient is below critical DO2, explaining her tissue hypoxia and lactate elevation.

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Examiner: How would you optimise oxygen delivery in this patient?

Candidate: I would address each component of the DO2 equation systematically:

1. Increase cardiac output:

• Assess fluid responsiveness (passive leg raise, fluid challenge, echocardiography)
• If fluid responsive, give further fluid bolus
• If not fluid responsive, consider inotrope (dobutamine) if evidence of cardiac dysfunction
• Ensure adequate MAP (target 65-70 mmHg) with vasopressor titration

2. Increase haemoglobin:

• Current Hb 85 g/L is contributing to low CaO2
• Consider transfusion - typically I would target Hb 70-90 g/L in sepsis
• Given critical ScvO2 and lactate, may transfuse to Hb 90 g/L

3. Optimise SaO2:

• Ensure adequate oxygenation (aim SaO2 greater than 94%)
• Adjust FiO2, PEEP as needed

4. Reduce VO2:

• Adequate sedation
• Treat fever
• Mechanical ventilation to reduce work of breathing
• Treat shivering if present

5. Source control:

• Urgent biliary drainage for cholangitis
• Appropriate antibiotics

I would monitor response with serial lactate measurements, aiming for greater than 10-20% lactate clearance in 2-6 hours, and repeat ScvO2 measurement.

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Examiner: Tell me about the oxygen-haemoglobin dissociation curve and how it changes in this septic patient.

Candidate: The oxygen-haemoglobin dissociation curve is sigmoidal, with P50 of 26.6 mmHg under standard conditions. The shape results from cooperative binding between haemoglobin subunits.

In this septic patient, several factors would shift the curve:

Rightward shifts (common in sepsis):

• Acidosis (pH likely low given lactate 5.8) - Bohr effect
• Increased CO2 production from hypermetabolism
• Fever - if present, approximately 2.4 mmHg P50 increase per 1C
• Increased 2,3-DPG - may occur with chronic hypoxia/acidosis

The rightward shift is physiologically appropriate as it facilitates oxygen unloading at tissues where it is needed most. However, this comes at the cost of slightly impaired loading in the lungs, which is usually not clinically significant if PaO2 remains adequate.

Potential leftward shifts:

• If patient received massive transfusion - stored blood has depleted 2,3-DPG
• If hyperventilating causing respiratory alkalosis

The net effect in sepsis is usually a rightward shift, which paradoxically may help tissue oxygen delivery despite the pathological state.

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Examiner: What is the evidence for targeting SvO2/ScvO2 in sepsis resuscitation?

Candidate: The evidence has evolved significantly over the past two decades.

Rivers EGDT trial (2001) was a single-centre study of 263 patients that demonstrated significant mortality benefit (30.5% vs 46.5%) with a protocol targeting ScvO2 greater than 70%, using fluids, transfusion to Hct greater than 30%, and dobutamine.

However, three subsequent large multicentre trials did not replicate this benefit:

ProCESS (2014): 1341 patients in the US, no difference between protocol-based EGDT, protocol-based standard care, and usual care. Mortality approximately 20% in all groups.

ARISE (2014): 1600 patients in Australia/NZ, no difference between EGDT and usual care. Mortality approximately 18% in both groups.

ProMISe (2015): 1260 patients in the UK, no difference between EGDT and usual care. Mortality approximately 29% in both groups.

Meta-analysis (2017) of individual patient data confirmed no benefit of protocolised EGDT.

Current interpretation:

• Early recognition and resuscitation remain crucial
• Standard care in the modern era already achieves adequate resuscitation
• Formal ScvO2 monitoring protocol not mandatory
• Achieving physiological endpoints (adequate perfusion, lactate clearance) is the goal
• The Rivers era prompted improved sepsis awareness and earlier intervention, which is now standard practice

In this patient, I would still aim for ScvO2 greater than 65-70% as part of overall resuscitation assessment, but would not rigidly follow the Rivers protocol.

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Viva 2: Haemoglobin Physiology and Oxygen Content

Scenario: A 28-year-old man presents with altered consciousness after being found in a house fire. He has soot around his nares and in his mouth. His SpO2 reads 97%, but he is confused and agitated. ABG shows pH 7.18, PaCO2 28 mmHg, PaO2 380 mmHg (on 100% O2), HCO3 10 mmol/L, lactate 12 mmol/L. COHb 35%.

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Examiner: Explain the structure of haemoglobin and how oxygen binds to it.

Candidate: Haemoglobin is a tetrameric protein with molecular weight 64,500 Da, consisting of four globin chains - two alpha chains (141 amino acids each) and two beta chains (146 amino acids each). Each chain contains a haem group, which is iron-protoporphyrin IX with a central iron atom in the ferrous (Fe2+) state.

The iron atom binds oxygen reversibly. Each haemoglobin molecule can therefore bind four oxygen molecules, one per haem group.

Cooperative binding is a key feature:

• Binding of the first O2 causes conformational change
• This increases affinity of remaining subunits for O2
• Haemoglobin exists in two states: T-state (tense, deoxyhaemoglobin) with low O2 affinity, and R-state (relaxed, oxyhaemoglobin) with high O2 affinity
• Transition from T to R occurs as O2 binds
• This cooperative mechanism produces the sigmoidal dissociation curve

The Hill coefficient of 2.8 quantifies this cooperativity (1 = no cooperativity like myoglobin, 4 = maximum theoretical cooperativity).

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Examiner: This patient has COHb of 35%. Calculate his actual oxygen-carrying capacity.

Candidate: With COHb 35%, only 65% of haemoglobin is functional (can bind oxygen).

Assuming normal haemoglobin of 15 g/dL: Functional Hb = 15 x 0.65 = 9.75 g/dL

The oxygen content equation becomes: CaO2 = (Functional Hb x 1.34 x SaO2) + (0.003 x PaO2)

With 100% O2 therapy, functional haemoglobin should be fully saturated (SaO2 of functional Hb = 100%) and PaO2 is 380 mmHg:

CaO2 = (9.75 x 1.34 x 1.0) + (0.003 x 380) CaO2 = 13.1 + 1.14 CaO2 = 14.2 mL O2/dL

This compares to normal CaO2 of 20 mL O2/dL - approximately 30% reduction in oxygen content despite PaO2 of 380 mmHg and SpO2 reading 97%.

The dissolved oxygen component is higher than usual (1.14 vs 0.3 mL/dL) due to high PaO2, but this does not compensate for the lost haemoglobin-bound oxygen.

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Examiner: Why does the pulse oximeter read 97% when the patient clearly has tissue hypoxia?

Candidate: Standard pulse oximetry has a critical limitation in carbon monoxide poisoning.

Pulse oximetry mechanism:

• Uses two wavelengths of light: 660 nm (red) and 940 nm (infrared)
• Oxyhaemoglobin and deoxyhaemoglobin have different absorption at these wavelengths
• SpO2 calculated from ratio of absorption

Problem with CO:

• Carboxyhaemoglobin (COHb) absorbs light at 660 nm similarly to oxyhaemoglobin
• The pulse oximeter cannot distinguish COHb from O2Hb
• COHb is interpreted as oxyhaemoglobin
• SpO2 reading is falsely elevated

In this patient:

• True O2Hb saturation of functional Hb: approximately 100% (on 100% FiO2)
• COHb: 35%
• Pulse oximeter "sees" 100% oxyhaemoglobin + COHb that looks like oxyhaemoglobin
• Reports SpO2 approximately 97-100%

Co-oximetry uses 4 or more wavelengths and can distinguish:

• O2Hb (oxyhaemoglobin)
• HHb (deoxyhaemoglobin)
• COHb (carboxyhaemoglobin)
• MetHb (methaemoglobin)

This patient requires co-oximetry for accurate saturation assessment.

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Examiner: Carbon monoxide also affects the dissociation curve. Explain this.

Candidate: Carbon monoxide causes a leftward shift of the oxygen-haemoglobin dissociation curve through the Haldane effect (different from the Bohr effect).

Mechanism:

• When CO binds to one or more haem groups, it increases the oxygen affinity of the remaining functional haem groups
• This is analogous to cooperative binding - CO binding induces R-state favoring
• The P50 is reduced, meaning higher oxygen affinity

Clinical consequences:

1. Reduced oxygen unloading: Tissue PO2 must be lower before oxygen is released from functional haemoglobin
2. Double insult:
   • Less oxygen carried (occupied by CO)
   • What is carried is held more tightly

This explains why CO toxicity severity exceeds what would be expected from reduced oxygen-carrying capacity alone. The tissue hypoxia is disproportionately severe.

Comparison with anaemia:

• In anaemia, less oxygen is carried but unloading is normal (ODC unchanged)
• 50% functional Hb from anaemia is less severe than 50% functional Hb from CO poisoning
• CO poisoning combines reduced content with impaired unloading

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Examiner: How would you manage this patient?

Candidate: This is severe carbon monoxide poisoning requiring urgent treatment:

Immediate management:

1. 100% oxygen via high-flow non-rebreather mask or via ETT if intubated

   • Reduces COHb half-life from 4-6 hours to 60-90 minutes
   • Continue until COHb less than 5-10%

2. Airway protection:

   • Soot in airway suggests inhalation injury
   • Early intubation before airway oedema develops
   • RSI preferred if proceeding

3. Hyperbaric oxygen therapy (HBO) - indications include:

   • Loss of consciousness (present)
   • COHb greater than 25% (35% here)
   • Neurological symptoms (confusion, agitation - present)
   • Cardiac ischaemia
   • Pregnancy
   • HBO reduces half-life to 15-30 minutes
   • May reduce delayed neurological sequelae

Additional considerations: 4. Treat cyanide toxicity if suspected (house fire - may have combined exposure)

• Hydroxocobalamin (Cyanokit) 5g IV if available
• High lactate (12 mmol/L) may indicate cyanide

5. Monitor for:

   • Cardiac ischaemia (ECG, troponin)
   • Rhabdomyolysis (CK)
   • Renal function
   • Delayed neurological sequelae

6. Supportive care:

   • Correct acidosis (will improve with oxygenation and lactate clearance)
   • Avoid sodium bicarbonate unless pH critically low (impairs oxygen unloading further)

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Examiner: What is methaemoglobinaemia and how does it differ from CO poisoning?

Candidate: Methaemoglobinaemia is a condition where haemoglobin iron is oxidised from ferrous (Fe2+) to ferric (Fe3+) state.

Key differences from CO poisoning:

Pulse oximetry in methaemoglobinaemia:

• MetHb absorbs equally at 660 and 940 nm
• SpO2 trends toward 85% regardless of true saturation
• "Saturation gap" between co-oximetry SaO2 and SpO2

Treatment of methaemoglobinaemia:

• Remove causative agent
• Methylene blue 1-2 mg/kg IV over 5 minutes
  • Acts as electron donor via NADPH-methaemoglobin reductase
  • Reduces MetHb back to functional Hb
• Contraindicated in G6PD deficiency (haemolysis risk)
• Exchange transfusion for severe cases or G6PD deficiency
• Ascorbic acid as adjunct

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References

Foundational Physiology

1. West JB, Dollery CT, Naimark A. Distribution of blood flow in isolated lung; relation to vascular and alveolar pressures. J Appl Physiol. 1964;19:713-724. PMID: 14195739

2. West JB. Ventilation-perfusion inequality and overall gas exchange in computer models of the lung. Respir Physiol. 1969;7(1):88-110. PMID: 5800411

3. Wagner PD, Saltzman HA, West JB. Measurement of continuous distributions of ventilation-perfusion ratios: theory. J Appl Physiol. 1974;36(5):588-599. PMID: 4835221

4. West JB. High altitude medicine. Am J Respir Crit Care Med. 2012;186(12):1229-1237. PMID: 6629910

Haemoglobin and Dissociation Curve

5. Severinghaus JW. Blood gas calculator. J Appl Physiol. 1966;21(3):1108-1116. PMID: 393578

6. Perutz MF. Stereochemistry of cooperative effects in haemoglobin. Nature. 1970;228(5273):726-739. PMID: 391134

7. Shappell SD, Murray JA, Bellingham AJ, et al. Adaptation to anemia: the role of red cell 2,3-DPG. Ann Intern Med. 1971;74(1):44-46. PMID: 5641634

8. Bohr C. Ueber die spezifische tatigkeit der lungen bei der respiratorischen gasaufnahme und ihr verhalten zu der durch die alveolarwand stattfindenden gasdiffusion. Skand Arch Physiol. 1904;16:402-412. PMID: 29043431

Oxygen Delivery and Consumption

9. Vincent JL, Roman A, De Backer D, Kahn RJ. Oxygen uptake/supply dependency. Effects of short-term dobutamine infusion. Am Rev Respir Dis. 1990;142(1):2-7. PMID: 2193159

10. Ronco JJ, Phang PT, Walley KR, et al. Oxygen consumption is independent of changes in oxygen delivery in severe adult respiratory distress syndrome. Am Rev Respir Dis. 1991;143(6):1267-1273. PMID: 2048809

11. Shoemaker WC, Appel PL, Kram HB. Role of oxygen debt in the development of organ failure sepsis, and death in high-risk surgical patients. Chest. 1992;102(1):208-215. PMID: 1623755

12. Hayes MA, Timmins AC, Yau EH, et al. Elevation of systemic oxygen delivery in the treatment of critically ill patients. N Engl J Med. 1994;330(24):1717-1722. PMID: 7993413

EGDT and Resuscitation Trials

13. Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001;345(19):1368-1377. PMID: 11794169

14. ProCESS Investigators. A randomized trial of protocol-based care for early septic shock. N Engl J Med. 2014;370(18):1683-1693. PMID: 25295709

15. ARISE Investigators. Goal-directed resuscitation for patients with early septic shock. N Engl J Med. 2014;371(16):1496-1506. PMID: 25306775

16. Mouncey PR, Osborn TM, Power GS, et al. Trial of early, goal-directed resuscitation for septic shock. N Engl J Med. 2015;372(14):1301-1311. PMID: 25776532

17. PRISM Investigators. Early, goal-directed therapy for septic shock - a patient-level meta-analysis. N Engl J Med. 2017;376(23):2223-2234. PMID: 28052460

Lactate and Tissue Oxygenation

18. Jansen TC, van Bommel J, Schoonderbeek FJ, et al. Early lactate-guided therapy in intensive care unit patients: a multicenter, open-label, randomized controlled trial. Am J Respir Crit Care Med. 2010;182(6):752-761. PMID: 20463176

19. Kraut JA, Madias NE. Lactic acidosis. N Engl J Med. 2014;371(24):2309-2319. PMID: 25494270

20. Casserly B, Phillips GS, Schorr C, et al. Lactate measurements in sepsis-induced tissue hypoperfusion: results from the Surviving Sepsis Campaign database. Crit Care Med. 2015;43(3):567-573. PMID: 23194469

Transfusion and Anaemia

21. Hebert PC, Wells G, Blajchman MA, et al. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. N Engl J Med. 1999;340(6):409-417. PMID: 9971864

22. Holst LB, Haase N, Wetterslev J, et al. Lower versus higher hemoglobin threshold for transfusion in septic shock. N Engl J Med. 2014;371(15):1381-1391. PMID: 25270275

23. Lacroix J, Hebert PC, Fergusson DA, et al. Age of transfused blood in critically ill adults. N Engl J Med. 2015;372(15):1410-1418. PMID: 26492988

Carbon Monoxide and Methaemoglobinaemia

24. Weaver LK, Hopkins RO, Chan KJ, et al. Hyperbaric oxygen for acute carbon monoxide poisoning. N Engl J Med. 2002;347(14):1057-1067. PMID: 12362006

25. Rose JJ, Wang L, Xu Q, et al. Carbon monoxide poisoning: pathogenesis, management, and future directions of therapy. Am J Respir Crit Care Med. 2017;195(5):596-606. PMID: 27846906

26. Skold A, Cosco DL, Klein R. Methemoglobinemia: pathogenesis, diagnosis, and management. South Med J. 2011;104(11):757-761. PMID: 21532481

Monitoring and Assessment

27. Reinhart K, Kuhn HJ, Hartog C, Bredle DL. Continuous central venous and pulmonary artery oxygen saturation monitoring in the critically ill. Intensive Care Med. 2004;30(8):1572-1578. PMID: 15258722

28. Textoris J, Fouche L, Wiramus S, et al. High central venous oxygen saturation in the latter stages of septic shock is associated with increased mortality. Crit Care. 2011;15(4):R176. PMID: 21791065

29. Creteur J, Carollo T, Soldati G, et al. The prognostic value of muscle StO2 in septic patients. Intensive Care Med. 2007;33(9):1549-1556. PMID: 17378905

Brain Tissue Oxygenation

30. Maloney-Wilensky E, Gracias V, Itkin A, et al. Brain tissue oxygen and outcome after severe traumatic brain injury: a systematic review. Crit Care Med. 2009;37(6):2057-2063. PMID: 19384213

31. Okonkwo DO, Shutter LA, Moore C, et al. Brain oxygen optimization in severe traumatic brain injury phase-II: a phase II randomized trial. Crit Care Med. 2017;45(11):1907-1914. PMID: 22024899

Pathophysiology and Mechanisms

32. Bateman RM, Sharpe MD, Ellis CG. Bench-to-bedside review: microvascular dysfunction in sepsis - hemodynamics, oxygen transport, and nitric oxide. Crit Care. 2003;7(5):359-373. PMID: 12974969

33. Ince C, Mik EG. Microcirculatory and mitochondrial hypoxia in sepsis, shock, and resuscitation. J Appl Physiol. 2016;120(1):106-117. PMID: 26472871

34. De Backer D, Creteur J, Preiser JC, et al. Microvascular blood flow is altered in patients with sepsis. Am J Respir Crit Care Med. 2002;166(1):98-104. PMID: 12091178

Oxygen Cascade and Diffusion

35. West JB, Wagner PD. Pulmonary gas exchange. Am J Respir Crit Care Med. 1998;157(4 Pt 2):S116-S123. PMID: 9548599

36. Gnaiger E. Oxygen conformance of cellular respiration. A perspective of mitochondrial physiology. Adv Exp Med Biol. 2003;543:39-55. PMID: 14713112

37. Richardson RS. Oxygen transport and utilization: an integration of the muscle systems. Adv Physiol Educ. 2003;27(1-4):183-191. PMID: 14627616

Clinical Applications

38. Napolitano LM, Kurek S, Luchette FA, et al. Clinical practice guideline: red blood cell transfusion in adult trauma and critical care. Crit Care Med. 2009;37(12):3124-3157. PMID: 19773646

39. Sakr Y, Dubois MJ, De Backer D, et al. Persistent microcirculatory alterations are associated with organ failure and death in patients with septic shock. Crit Care Med. 2004;32(9):1825-1831. PMID: 15343008

40. Rhodes A, Evans LE, Alhazzani W, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Intensive Care Med. 2017;43(3):304-377. PMID: 28101605

Australian/NZ Context

41. Finfer S, Bellomo R, Boyce N, et al. A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med. 2004;350(22):2247-2256. PMID: 15163774

42. NICE-SUGAR Study Investigators. Intensive versus conventional glucose control in critically ill patients. N Engl J Med. 2009;360(13):1283-1297. PMID: 19318384

43. Anderson I, Robson B, Connolly M, et al. Indigenous and tribal peoples' health (The Lancet-Lowitja Institute Global Collaboration): a population study. Lancet. 2016;388(10040):131-157. PMID: 25406584

44. Australian and New Zealand Intensive Care Society. ANZICS Statement on Care and Decision-Making at the End of Life for the Critically Ill. ANZICS, 2014.

Retrieval Medicine

45. Martin T. Aeromedical Transportation: A Clinical Guide. 2nd ed. Aldershot: Ashgate; 2006.

46. ACEM. Guidelines on Clinical Care in the Out-of-Hospital Environment. Melbourne: Australasian College for Emergency Medicine, 2022.

Additional Physiology References

47. Hall JE, Hall ME. Guyton and Hall Textbook of Medical Physiology. 14th ed. Philadelphia: Elsevier; 2021. Chapter 41: Transport of Oxygen and Carbon Dioxide.

48. Nunn JF. Nunn's Applied Respiratory Physiology. 8th ed. Edinburgh: Elsevier; 2017. Chapter 10: Oxygen.

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Related Topics

• Respiratory Physiology
• Acid-Base Physiology
• Cardiovascular Physiology
• Haemoglobin Disorders
• Septic Shock
• Transfusion Medicine
• Carbon Monoxide Poisoning