Respiratory - Oxygen Transport Flashcards
What is Huffner’s constant?
It is the measured maximum oxygen carrying capacity of haemoglobin.
1.34 ml O2 / gram Hb
How is O2 transported in blood - give proportions
Bound to Hb - 98%
Dissolved in plasma - 2%
What is the Oxygen content equation
CaO2 = {1.34 x [Hb] x SaO2/100%} +0.023 x PO2
This equation gives ml of O2 per 100 ml of blood
CaO2 = 19.8 ml O2 per 100 ml blood CvO2 = 15.2 ml O2 per 100 ml blood
What is Henry’s law in the context of O2 transport
The volume of O2 dissolved in blood is proportional to the partial pressure of O2
Why is dissolved O2 important despite being such small percentage of O2 in transit. Quote Fick’s law in the explanation
The PaO2 is determined from the amount of O2 dissolved in plasma - PO2 within RBC is small as O2 is bound to Hb.
Fick’s law of diffusion states diffusion occurs along a pressure gradient - so O2 diffuses into the tissues from the dissolved portion in the plasma, not from Hb itself. O2 dissociates from Hb to replenish the plasma O2.
How do the body’s O2 stores compare with its consumption of O2
70 kg adult STORES: 1. Blood - 850 ml O2 2. Myoglobin - 250 ml O2 3. Lungs - 450 ml O2
Total 1550 ml
CONSUMPTION
1. 250 ml/min at rest
1550 ml O2 divided by 250 ml/minute
= ± 6 minutes
O2 consumption increased in kids
Reduced O2 carrying capacity –>anaemia / CO poisoning
Describe the structure of red blood cells
Small, flexible, biconcave discs of diameter 6 - 8 micrometers that are able to deform enough to squeeze through the smallest capillaries around 3 micrometers in diameter.
Cell membrane has NB Ag’s NB in blood transfusion medicine: ABO (cell surface CHO based Ags) and Rhesus (Transmembrane proteins)
Why are red blood cells unique cells
- No nucleus
- No mitochondria therefore anaerobic metabolism –> depend entirely on glucose and the glycolytic pathway
‘bags of Hb’
Nucleus is lost in the latter stages of maturation in the bone marrow during erythropoiesis (reticulocytes)
What percentage of circulating RBC’s are reticulocytes?
1% normally –> may increase if the bone marrow is highly active e.g. haemorrhage or haemolytic anaemia
Describe the structure of HbA
Quaternary structure (Tetrahedral)
- 4 polypeptide globin subunits (2 alpha and 2 beta chains)
- Globin chains held together by weak electrostatic forces
- Each globin chain has:
1. Haem group (iron containing porphyrin ring with iron in the Ferrous state Fe2+)
2. O2 molecules are bound to each haem group
How many O2 molecules can bind to one Hb molecule
Four - One bound to each haem group (Fe2+ ion)
What is co-operative binding
Increase in O2 affinity of Hb with each successive O2 binding
The last of 4 O2 molecules to bind binds 300 times more easily than the first
This results in the sigmoid shaped curve of the OHDC and when four O2 molecules are bound the Hb is in the ‘relaxed’ as opposed to the tense conformation
What is the OHDC and why is its sigmoid shape clinically relevant?
OHDC describes the relationship between SaO2 and blood O2 tension.
Distal - plateau portion curve large changes in PaO2 with minimal change to SaO2.
Initial steep part of the curve - small changes in PaO2 –> large changes in SaO2.
Describe the causes of left and right shift of the P50 on the OHDC
RIGHT SHIFT
High H+ (acidosis) High CO2 High temperature 2,3 DPG HbS Exercise
LEFT SHIFT
Low H+ (Alkalosis) Low CO2 Low temperature Low 2,3, DPG MetHb COHb HbF
What is the Bohr effect
Metabolically active tissues produce CO2, H ions and heat –. blood arrives at capillaries and is exposed to this –> OHDC shifts right –> offloading O2 where it is most needed
What is 2,3 DPG and what is its role in altering O2 binding to Hb
When cellular O2 falls –> anaerobic metabolism –> glycolysis: glucose converted to pyruvate for 2 x ATP.
One of the intermediates in the glycolytic pathway is converted to 2,3 DPG by phosphofruktokinase.
2,3 DPG binds to the beta chains on deoxyHb stabilizing it in this configuration –> this means that O2 is offloaded to cells undergoing anaerobic metabolism.
2.3 DPG cannot bind to gamma chains in HbF therefore assisting with HbF to have a needed higher affinity to O2 than the HbA of the mothers Hb.
Why is understanding the mechanism of 2,3, DPG important to clinical practice
Stored blood –> 1 - 2 weeks of storage = almost negligable amounts of 2,3 DPG. Therefore when the blood is transfused it is left shifted and cannot release O2. It takes 24 hours for the 2,3 DPG to normalize. Therefore, a transfusion 24 hours prior to surgery may be more advantageous to gain the full benefit of the transfusion.
In contrast - cell salvaged blood - maintains all 2,3, DPG O2 affinity and offloading are unaffected.
Classify the forms of Hb
Physiological
- HbA (A2B2)
- HbA2 ( A2Delta2)
- HbF (A2Gamma2)
Pathological
- HbS (abnormal beta globin subunit)
- MetHb (Fe3+ instead Fe2+)
- COHb (CO molecules)
- CyanoHb (Cyanide ions)
Why does HbF have a higher affinity for oxygen than HbA
- HbF causes a leftward shift of the OHDC
- 2,3 DPG binds to beta globin chains. Beta globin chains are replaced by gamma globin chains in HbF, therefore there is no where for 2,3 DPG to bind. Therefore the Hb molecule remains in a ‘relaxed’ rather than ‘tense’ confirmation increasing the affinity of HbF to O2.
What is the difference between sickle cell trait and sickle cell disease
Inherited autosomal recessive disease
Homozygotes have point mutations on both Beta-globin chains = sickle cell disease = symptomatic patients
Heterozygotes have a point mutation on only one of the Beta-globin chains = sickle cell trait = asymptomatic patients
Describe the genetic abnormality and that results in Sickle cell disease
Chromosome 11 beta-globin gene point mutation on the codon encoding the amino acid at position 6 resulting in the replacement of glutamate with valine.
This substitution results in a drastic change in the way the red cell behaves in hypoxic conditions –> Hb molecules aggregate and distort into a sickle shape: i.e. when moving from arterial to venous blood (especially in the sluggish flow within the spleen). Repetitive aggregation - de-aggregation –> reduced RBC membrane elasiticity.
Describe the pathophysiology of Sickle Cell disease
Chromosome 11 beta-globin gene point mutation on the codon encoding the amino acid at position 6 resulting in the replacement of glutamate with valine.
This substitution results in a drastic change in the way the red cell behaves in hypoxic conditions –> Hb molecules aggregate and distort into a sickle shape: i.e. when moving from arterial to venous blood (especially in the sluggish flow within the spleen). Repetitive aggregation - de-aggregation –> reduced RBC membrane elasiticity.
Reduce elasticity --> 1. VASCULAR OCCLUSION - Capillary and venous occlusion threaten whole organ infarction --> ischaemic pain and organ dysfunction. E.g. in childhood: vascular occlusion results in splenic infarction --> increased susceptibility to encapsulated bacterial infection (e.g. meningococcal septicaemia) Rx: 1. Analgaesia 2. Hydration + IVF 3. Blood exchange transfusion
2. REDUCED RBC SURVIVAL Chronic heamolysis: - N RBC survives 100 - 120 days - HbS RBC survives 10 - 20 days [Hb] 7 - 11 with reticulocytosis
Aplastic crises
- Parvovirus B19
Describe the mechanism of ‘aplastic crisis’ in sickle cell disease
Chronic haemolytic anaemia due to reduced elasticity of RBC membrane (repetitive aggregation and de-aggregation RBCs): RBC life span is 10 - 20 days in sickle cell disease. Normal RBC lifespan is 100 - 120 days.
Parvovirus B19 infection briefly stops erythropoiesis by destroying RBC precursors –> preventing RBC production for 2-3 days. Normally clinically unimportant but in Sickle Cell disease brief cessation of bone marrow production can lead to profound anaemia.
Summarise the anaesthetic management of a patient with sickle cell disease
Identify undiagnosed sickle cell disease
‘sickledex test’ –> Can only ID sickle trait
PREOP
Correct precipitants: hypoxia/acidosis/hypothermia/hypotension
Exchange transfusion if there is time
INTRAOP Avoid precipitants: hypoxia/acidosis/hypothermia/hypotension Avoid tourniquets Regional anaesthesia advantageous
POSTOP
HCU/FiO2/Warmers/Fluids
Analgaesia challenging (sickle cell patient’s rarely opioid naive).
What is the normal level of MetHb in the body and what is MetHb
MetHb = Methaemaglobin which contains a Ferric (Fe3+) ion instead of a Ferrous (Fe2+)
OIL RIG (Oxidation is Loss Reduction is Gain)
Normally: 1% Hb is MetHb
What maintains the low level of MetHb in circulation
- Glutathione/NADPH system
- Oxidizing agents within RBC are reduced before they are able to oxidise the haem Fe2+ to Fe3+.
- Pentose Phosphate Pathway is NB as it supplies NADPH to return glutathione to its reduced form. - MetHb reductase/NADH system
MetHb (Fe3+) formed is returned back to Fe2+ by MetHb reductase and NADH.
When does Methaemoglobinaemia occur
TOO MANY OXIDISING AGENTS
- Sulphonamide antibioitcs
- NO
- Amide local anaesthetics (Prilocaine)
DEFECTIVE ANTI-OXIDANT SYSTEMS
- G6PD
- PPP defective
What are the clinical problems that arise from MetHb
- MetHb cannot bind O2 = functional anaemia
- Altered O2 binding affinity of normal Hb –> Left shifted OHDC –> failure to offload O2
SaO2 read 85%.
For accurate MetHb concentration, a CO-oximeter is required.
What is the Treatment of Methaemoglobinaemia
Mild - Supplemental O2
Severe - Supplemental O2 + Methylene blue
How does carbon monoxide bind to the haemoglobin molecule?
Binds REVERSIBLY, like O2, the the Fe2+ ion. (Cyanide binds IRREVERSIBLY)
How does haemoglobin’s affinity for CO compare to that for O2 and how is the OHDC affected
Hb’s affinity for CO is 250 times higher. So COHb is preferentially formed over oxy-haemoglobin resulting in reduced O2 carrying capacity
OHDC shits to the left –> reduced offloading of O2 to tissues
What is the normal level of COHb in the blood and what causes higher levels. What are the clinical features related to higher levels of CO in the blood
< 2% Normal
9% Heavy smokers
>9% House fires/Gas appliances/Car fumes
Clinical effects
15 - 20 % - Headache and confusion
20 - 60% - Weakness/dizziness/N + V
>60% - Convulsions/coma/death
Do patients with CO poisoning appear cyanosed?
No. Cyanosis is only evident when there is at least 5g/dL of deoxyHb. Any Hb that is not bound to CO is usually saturated with O2.
Rarely patients have a cherry red discoloration of skin and mucous membranes
What are the mechanisms of cyanide toxicity
- Reduced O2 carrying capacity
- Irreversible binding to Fe2+ –> functional anaemia - Inhibition of the electron transport chain
- Inhibition of cytochrome c oxidase (Complex IV) of the ETC.
In Summary:
Reduced O2 carrying capacity
Mitochondria unable to use O2 that reaches them.
When clinical/biochemical parameters might indicate the presence of cyanide toxicity
Bright red venous blood with high SaO2 as blood as passed through tissue without offloading O2.
Raised ScvO2 with lactic acidosis resulting from anaerobic metabolism
What causes cyanide toxicity
- Smoke inhalation from burning nylon
- Sodium Nitroprusside administration (ICU)
- Industrial setting
What is the treatment of Cyanide poisoning
- Convert Fe2+ to Fe3+: AMYL NITRITE
- Instead of binding to cytochrome c oxidase cyanide preferentially binds to MetHb forming: Cyanmethaemoglobin. SODIUM THIOSULPHATE converts cyanmetHb to Hb. - Chelation
- DICOBALT EDETATE - SODIUM THIOSULPHATE converts cyanide to thiocyanate which is water soluble and excreted in the urine
What about myoglobin: what is its structure and oxygen-binding profile?
Myoglobin structure
- 1 globin chain
- 1 haem group with Fe2+
Myoglobin location
- skeletal muscle
- Myoglobin Fe2+ pigments give red colour to red meats
Myoglobin oxygen binding profile
- Oxymyoglobin dissociation curve = hyperbolic (no co-operative binding like Hb). The P50 of the curve is significantly to the left of the Hb P50 and the shape is hyperbolic, not sigmoid like OxyHb dissociation curve.
