Respiratory physiology: Co2 Carriage in Blood and Acid-Base Equilibrium

Question 1

Describe therelationship between pH and hydrogen ion concentration

Answer 1

relationship between pH and hydrogen ion concentration ([H+]) is logarithmic:

• pH = -log10[H+]
• every change in pH of 1 unit equals a ten fold change in the hydrogen ion concentration

Question 2

Definition of a buffer:

Answer 2

• a solution that can minimise changes in the free H+ concentration and therefore change in pH.
• usually comprise a weak acid and its base in equilibrium:
  
  • weak acid ↔ H+ + weak base
• The most common buffer in biological systems is bicarbonate:
  
  • H2CO3 ↔ H+ + HCO3-

Question 3

Carbon Dioxide

1. Production-> excretion
2. 3 systems by whoch it’s transported in blood

Answer 3

• Produced by Krebs cycle during aeobic metabolism
• diffuses down a series of partial pressure gradients through the cytoplasm and the extracellular fluid into the blood
• In the lungs, the PCO2 of the blood in the pulmonary capillaries is higher than the alveolar PCO2
• carbon dioxide diffuses from the blood into the alveolar gas and is excreted

three systems by which CO2 is carried by blood:

1. In physical solution
2. By direct binding to proteins (carbamino carriage)
3. As bicarbonate ions

Question 4

Carriage of Carbon Dioxide: In Physical Solution

Answer 4

• CO2 is moderately soluble in water and by Henry’s law of solubility:
  
  • PCO2 × solubility coefficient = CO2 concentration in solution
• solubility coefficient of carbon dioxide (α) is expressed in units of mmol/L/kPa (or mmol/L/mmHg)
• value depends on temperature, being 0.231 at 37°C.
• contribution of dissolved carbon dioxide to the total carriage of the gas in blood is small
• Total CO2 in 1L blood (mmol/L) = 21.50
• Total CO2 in 1L mixed venous blood (mmol/L) = 23.30

Question 5

Decribe the formation of bicarbonate ions from dissolved CO2

Answer 5

Stage 1

• CO₂ + H₂O ↔ H₂CO₃

Stage 2

• H₂CO₃ ↔ H⁺ + HCO₃⁻

Final dissociation into carbonate occurs at high pH (above 9)

• H⁺ + HCO₃⁻ ↔ 2H⁺ + CO₃²⁻

In biological systems the equilibrium of this reaction is far to the left with less than 1% of the molecules of carbon dioxide being in the form of carbonic acid

reaction is catalysed in both directions by an enzyme carbonic anhydrase (CA)

Carbonic Anhydrase

• 16 isoenzymes of CA
• Types I and II in RBCs
• low molecular weight zinc-containing enzyme

Question 6

Carbonic anhydase

Decscribe

Mechanism

Answer 6

Carbonic Anhydrase

• 16 isoenzymes of CA
• Types I and II in RBCs
• low molecular weight zinc-containing enzyme
• FAST
• maximum speed is determined only by the ability of the surrounding buffers to provide/remove H+ ions to/from the enzyme

Molecular mechanism

1. The Zn atom hydrolyses water to produce a reactive Zn-OH- species
2. Nearby histidine molecule removes H+ from the zinc and transfers it to any buffer molecule nearby
3. CO2 then combines with Zn-OH- to produce HCO3-
4. The HCO3- dissociated from the zinc atom

Question 7

Acetazolamide

Answer 7

• inhibits carbonic anhydrase
• non-specific for the different CA isozymes
• inhibits CA in all organs at a dose of 5–20 mg/kg
• revelaed CA not essential to life
• More then 98% of CA action blocked to see change in CO2 transport
• used by mountaineers to treat altitude sickness
  
  • interferes with CO2 transport
  • intracellular PCO2 increases
  • drives ventilation
  • accelerates acclimatization

Question 8

Quantify the dissociation equation;

H2CO3 ↔ H+ + HCO3⁻

Answer 8

Question 9

Carbamino Carriage

Answer 9

• Amino groups in the uncharged R–NH2 form can combine with CO2
• form carbamic acid
• at body pH dissociates to carbamate
• constitutes a buffer system
• single terminal amino group in each protein chain can bond with CO2
• the side chain amino groups that are found in lysine and arginine
• hydrogen ions and CO2 compete to react with uncharged amino group (pH dependant)
• Almost all blood carbamino carriage is in combination with haemoglobin
• Deoxyhaemoglobin is about 3.5 times as effective as oxyhaemoglobin (Haldane effect)

Question 10

Carbamino carriage and The Haldane effect

Answer 10

• amount of carbon dioxide carried in the blood by carbamino carriage is small
• the difference between the amount carried in venous and arterial blood is about a third of the total arterial/venous difference
• accounts for the major part of the Haldane effect
• remainder being due to the increased buffering capacity of reduced haemoglobin

Physiological importance of the Haldane effect:

• As blood passes along a systemic capillary and the O2 saturation progressively decreases, the Haldane effect means that the ability of blood to carry CO2 progressively improves along the capillary. The converse effect occurs along a pulmonary capillary.

Question 11

Histidine

Answer 11

• only amino acid to be an effective buffer at physiological pH
• imidazole group on histidine contribute to the considerable buffering power of haemoglobin
• Each haemoglobin tetramer includes 38 histidine molecules
• buffering power of plasma proteins is less and is directly proportional to their histidine content
• dissociation constant of the histidine molecule is strongly influenced by the state of oxygenation of the haem
  
  • deoxyhaemoglobin = more basic
  • oxyhaemoglobin = more acidic -> weak bond
• Resulting in:
  
  • O2 dissociates from Hb becoming more basic -> binds to H+
  • H+ removed accelerating HCO3- production
  • improves carraige of CO2 (Haldane effect)
  • Conversion to basic histidne -> increased affinity of haem for O2 (Bohr effect)

Question 12

Within the plasma there is almost no chemical combination of carbon dioxide because?

Answer 12

• There is no carbonic anhydrase in plasma so carbonic acid is formed only very slowly
• There is little buffering power in plasma to promote the dissociation of carbonic acid
• The formation of carbamino compounds by plasma proteins is minimal and almost identical for arterial and venous blood

Question 13

Carbon dioxide can diffuse freely into the RBC where what two things may occur?

Answer 13

increasing intracellular PCO2

1. increase carbamino carriage of CO2 by haemoglobin; effect greatly enhanced by the fall in oxygen saturation
2. presence of carbonic anhydrase in the RBC CO2is rapidly hydrated to carbonic acid, which dissociates into bicarbonate ions.

Question 14

Hydration of CO2 in the RBC causes accumulation of hydrogen and bicarbonate ions. If not removed from the cell these will quickly tip the equilibrium of the reaction against further dissociation of carbonic acid, a situation that is avoided in the RBC what two mechanisms?

Answer 14

1. Haemoglobin buffering: H+ ions froduced are buffered by histidine molecules on Hb. Effect enhanced in deoxyhaemoglobin
2. Hamburger shift:

• Excess HCO3- ions in the RBC are actively exported from the cell in exchange for chloride ions
• maintain electrical neutrality across the membrane
• active process
• facilitated by a membrane bound protein named Band 3
• exchanges bicarbonate and chloride ions by a ‘ping-pong’ mechanism

Question 15

Band 3 Protein

Answer 15

• intimately associated with other RBC proteins
• anchoring site for cytoskeleton proteins that maintain the RBC shape and membrane stability
• inherited defect of Band 3 is responsible for hereditary spherocytosis in humans
• loosely bound to carbonic anhydrase; protein complex formed facilitates rapid channelling of HCO3- out of the cell by direct transfer between the two proteins

Question 16

Dissociation Curve for CO2

Answer 16

• The small contribution made by dissolved CO2
• The majority of the large amount of CO2 in blood is in the form of HCO3⁻
• Carbamino carriage is quantitatively small but the difference between arterial and venous blood makes this an important contributor to CO2 carriage in vivo

Question 17

CO2 carriage in hypothermia

Answer 17

• CO2 becomes more soluble in water as temperature decreases
• maintenance of the same PCO2 in blood when hypothermic will require a greater total CO2 content
• decreasing temperature reduces the ionisation of water into H+ and OH-ions
• pH increases by approximately 0.016 per °C fall in temperature
• If CO2 production and excretion remain constant, hypothermia would therefore be expected to result in alkalotic conditions in both the intra- and extra-cellular spaces

Question 18

Respiratory Acidosis

Causes of raised PCO2

Causes of ventilatory failure

Answer 18

• increase in the PCO2 of the blood and extracellular fluid
• long term-> renal compensation occurs and the bicarbonate concentration increases

Elevated PCO2 may result from one or more of

1. Increased inspired CO2:

• Inadequate fresh gas flow in non-invasive ventilation systems
• During anaesthesia: exhausted sodalime; malfunctioning of breathing system (e.g. stuck valves)

2. Increased production:
   * High temperature: sepsis, over-enthusiastic warming in theatre, malignant hyperthermia
   * Hyperthyroid states
   * Laparoscopic surgery (normal absorption = 50 ml per minute)
3. Decreased excretion:
   * Increased dead space
   
   • pathology such as pulmonary embolism
   • iatrogenic e.g. excessive catheter mount/filter volume during artificial ventilation in children
     * Iatrogenic during anaesthesia and ICU i.e. wrong ventilator settings
     * Ventilatory failure i.e. failure of the respiratory muscle pump or its control mechanism

Causes of ventilatory failure:

• upper motor neurone damage
• anterior horn cell disease eg poliomyelitis
• lower motor neurone damage eg GBS
• neuromuscular juntion eg MG
• respiratory muscles eg hyperinflation COPD
• loss elasticity lungs/chest wall
• loss structural integrity chest wall eg rib fractures
• small airway resistance asthma COPD
• upper airway obscruction

Question 19

Metabolic Acidosis

Answer 19

• excessive concentration of H+ ions in the extracellular fluid + exceeding buffer system capacity
• Compensation occurs hyperventilation

Sources of the extra acid include:

• Ketone bodies e.g. in diabetic keto-acidosis
• Lactate production e.g. in extreme exercise or shock
• Acid ingestion e.g. salicylate overdose
• Failure to excrete H+ ions i.e. renal failure
• Increased loss of bicarbonate e.g. gastrointestinal fistulae

Question 20

Respiratory Alkalosis

Answer 20

• low PCO2 which can only arise from an alveolar ventilation that is excessive relative to CO2 production

Common causes include:

• Iatrogenic eg incorrect ventilation settings
• hyperventilation from anxiety/hysteria
• Pathological causes eg pulmonary fibrosis, oedema, asthma
• SAH
• compensation for a different physiological problem

Question 21

Metabolic Alkalosis

Answer 21

• low H+ concentration in the extracellular fluid
• Causes include:
  
  • Excessive acid loss (vomiting). In most case of prolonged vomiting the pylorus is open and alkaline duodenal secretions are also lost. In neonatal pyloric stenosis this is not the case, and metabolic alkalosis may become pronounced
  • Ingestion of bicarbonate, usually from indigestion remedies
  • Citrate toxicity following massive transfusion