Respiratory: Gaseous Exchange: Hypoxia and Hyper- and Hypo-Capnia

Question 1

Arterial Blood Gas Values

1. Normal partial pressure for O2
2. Normal partial pressure for CO2
3. Hypoxaemia definition
4. What is hypoxia?

Answer 1

1. O2 = 13.3kPa
2. CO2 = 5.3kPa
3. Hypoxaemia is defined as an arterial PO2 below normal levels
4. Tissue hypoxia describes when the PO2 within the cells is insufficient to allow normal aerobic metabolism to provide energy for cellular functions. This may occur despite a normal arterial PO2.

Question 2

Causes of tissue hypoxia (4)

Answer 2

1. Hypoxic hypoxia
2. Anaemic hypoxia
3. Ischaemic hypoxia
4. Histotoxic hypoxia

Hypoxic hypoxia - is any cause of reduced oxygen availability to haemoglobin.

• Hypoxic atmosphere
  
  • low O2 tension at high altitude
• Hypoventilation
• V/Q mismatch
  
  • Shunt
  • Deadspace
• Reduced O2 diffusion in the lung
  
  • Loss of lung tissue e.g. emphysema
  • Thickening of alveolar membrane e.g. pulmonary oedema

Anaemic hypoxia - is defined as any cause of reduced oxygen carrying capacity in the blood, for example:

• Reduced erythrocyte count
  
  • Blood loss
  • Marrow suppression
• Reduced haemoglobin concentration
  
  • Iron deficiency
• Abnormal Hb
  
  • Sickle cell
• Reduced Hb/O2 binding
  
  • Carbon monoxide poisoning

Ischaemic hypoxia - also called circulatory or stagnant hypoxia, Hb and PO2 levels are normal, but tissue DO2 (oxygen delivery) is reduced. A greater proportion of O2 is extracted leading to an increase in arterio-venous O2 difference.

Causes include:

• Reduced cardiac output
  
  • Hypovolaemia
  • Primary cardiac failure
• Vascular abnormalities
  
  • Embolism/external compression
  • Arteriovenous shunting

Histotoxic hypoxia, oxygen delivery is maintained, but the cells are unable to utilize it, for instance in cyanide poisoning.

Question 3

What is cellular metabolism

Three phases

Answer 3

Energy for cell functions comes from high energy compounds eg ATP

Simple (two carbon) units of metabolic fuels, such as carbohydrate, fat and protein are catabolized to produce these high energy compounds.

This process can be divided into three phases:

Phase 1: The production of two carbon compounds

Phase 2: The citric acid cycle

Phase 3: The electron transport chain

Question 4

Cellular metabolism: Phase 1

Answer 4

Small components of metabolic fuels processed to produce 2 carbon compaounds for phase 2

Glucose

Glucose (6C) -> glycolysis -> 2 pyruvate (3C) (cytoplasm)

2 pyruvate (3C) -> oxidative carboxylation -> 2 acetylCoA (2C) + 2 CO2 (mitochondria)

Free fatty acids

Free fatty acids -> β oxidation -> AcetylCoA (mitochondria)

Amino acids

Amino acids -> oxidation -> pyruvate/AcetylCoA/Krebs cycle intermediates

Question 5

Cellular metabolism: Phase 2

Answer 5

Krebs cycle (citric acid cycle)

AcetylCoA + oxaloacetate -> citrate -> krebs cycle

Each glucose produces 2x acetylCoA so 2x krebs cycle

Final compound is oxaloacetate, allowing the cycle to start again.

Per glucose molecule the cycle produces:

2 ATP

6NADH₂⁺

2 FADH₂

4 CO2

(reduced molecules containing high energy electons)

Question 6

Cellular metabolism: Phase 3

Answer 6

The electron transport chain

Mitochondria

redcued enzymes re-oxidased

Releases

• electrons (passed down chain)
• energy -> converts ADP to ATP via oxidative phosphylation

NADH₂⁺ releases energy to convert 3 molecules ADP

FADH₂ releases energy to convert 2 molecules of ADP

Oxygen is the final electron acceptor -> H₂O

Question 7

Aerobic Respiration

Answer 7

All three phases proceed

Thirty eight molecules of ATP per glucose molecule

Question 8

Anaerobic Respiration

Answer 8

electron transfer chain ceases to operate and oxidative phosphorylation stops

NAD+ and FAD are not re-formed, and so the Krebs cycle cannot continue.

Only glycolysis can continue to produce ATP by substrate phosphorylation.

From anaerobic glucose metabolism total energy production is therefore:

Two molecules of ATP per glucose molecule

Question 9

ATP stores in the body will last?

What is the minimum PO2 for aerobic metabolism

Answer 9

Approx 90 seconds

Critical PO2 =0.4kPa

Question 10

Consequences of cellular hypoxia

Answer 10

Question 11

Draw the oxygen cascade

Answer 11

Question 12

Physiological Compensation for Hypoxia

Answer 12

EARLY

Local

• Bohr effect
  
  • right shift due to anaeorbic metabilsm producing acids -> decrease pH
  • increase 2,3-DPG
• vasodilatation
  
  • decrease pH, PO2,increase PCO2 and local metabolites (adenosine, K+)

Ventilatory

• peripheral chemoreceptors (carotid bodies) responding to fall in oxygen tension
• Hypoxic response
  
  • PO2 <7 -> increase minute ventilation
  • increase pCO2 -> increase minute ventilation

Cardiovascular

• perpheral chemoreceptors fall in O2 tension
• vasconstriction
• tachycardia
• -> increase CO and BP

LATE

• erythropoietin -> increase RBC (3-5 days)
• decrease O2 detected by renal peritubular interstitial cells
• 10% liver 90% kidneys

Question 13

Hypoxia and the brain

Answer 13

Brain tissue relies entirely on oxidative phosphorylation of glucose for energy. Therefore it is extremely sensitive to hypoxia.

The brain utilises 20% of total body O2 consumption.

Cerebral blood flow (CBF) is maintained constant over a mean arterial pressure range of 50–150 mmHg.

Normally CBF is not affected by changes in PO2. A fall in PO2 below 6.7 kPa leads to exponential increases in CBF.

The increase in CBF is due to local lactic acidosis/vasodilatation.

Question 14

Hypoxia and the heart

Answer 14

In coronary tissue, oxygen extraction is already very high at 75%, compared with 25% in other tissues.

Extraction can be increased as high as 90%, but if myocardial O2 need is high e.g. during exercise, or if hypoxia is present, O2 delivery must be maintained by increasing coronary blood flow.

Coronary blood flow may be increased by:

• Local metabolites causing arteriolar dilatation
• A direct effect of low O2 tension on arteriolar tone
• Myogenic control of arteriolar tone

Question 15

Pulmonary response to hypoxia

Answer 15

Pulmonary tissue and hypoxic pulmonary vasoconstriction (HPV)

Unlike other systemic blood vessels pulmonary vessels constrict in response to a low PO2, principally in the alveolus but also in the pulmonary artery.

This response is locally mediated, and multifactorial. It may involve:

• Inhibition of nitric oxide production
• Local production of vasoconstrictors such as endothelin
• A direct effect of hypoxia on vascular smooth muscle tone

HPV results in the diversion of blood to the more oxygenated areas of the lung, improving oxygen uptake and delivery.

Question 16

Normal ranges for PCO2

Answer 16

Arterial 4.7–5.3 kPa

Venous 6.1 kPa

Inspired PCO2 ≈ zero

Question 17

Factors Affecting PaCO2

Answer 17

1. Alveolar minute ventilation (AMV)
2. Tissue metabolism (CO2 production)

The very rapid equilibration of CO2 across the alveolus means that PaCO2 is much less affected by changes in V/Q than PaO2.

Question 18

Alveolar CO2

Answer 18

%alveolar PACO2= CO2 output x 100/VA

=200ml/min

4000ml/min

=5%

double VA = half PACO2

Question 19

PaCO2 and Blood pH

Define pH

How are PCO2 and [H⁺] related

Answer 19

pH = - Log10 [H+]

By changing the PCO2 the equation proceeds to the left or the right, and a constant hydrogen ion (pH) concentration can be achieved.

Question 20

Causes of Hypocapnia

Answer 20

Primary respiratory

• Hypoxia, caused by:
  
  • Low atmospheric O2
  • Congenital heart disease
  • Pneumonia
• Anxiety
• Pain

All of the above cause an increase in the alveolar minute ventilation. As the rate of CO2 production is unchanged the result is a decrease in end tidal and arterial PCO2.

Compensatory

Compensatory hypocapnia occurs in response to a metabolic acidosis. The possible causes of a metabolic acidosis include:

Addition of exogenous acid, e.g. salicylate

↑endogenous acid production e.g. lactate, ketoacids

↓excretion of normal acid production, e.g. renal failure

↑loss of base, e.g. bicarbonate

There is a compensatory increase in A to attempt to maintain the plasma pH in the normal range by reducing PaC02.

Question 21

Causes of Hypercapnia

Answer 21

Increased inspired CO2

• Increased inspired CO2 occurs principally during mechanical ventilation procedures, e.g.:
  
  • Re-breathing
  • Addition of exogenous CO2

Primary respiratory

• Primary respiratory causes of hypercapnia can generally be defined asany cause of a reduced VA:
  
  • CNS depression
  • Type 2 respiratory failure
  • Restrictive lung disease
  • Increase in respiratory dead space

Increased CO2 production

• In some circumstances, e.g. during anaesthesia and ventilation, increased CO2 production can occur without compensatory hyper-ventilation.
  
  • Sepsis
  • Malignant hyperthermia

Compensatory

• Compensatory causes are those that are secondary to metabolic alkalosis e.g.:
  
  • Loss of H+ ions, e.g. vomiting
  • Hypokalaemia → renal H+ excretion
  • Addition of exogenous alkali, e.g. bicarbonate

The minute ventilation is reduced to increase the PaCO2 and correct the pH. This is however limited by the hypoxic effect.

If the hypoventilation is severe enough to cause hypoxia below the threshold of approximately 7 kPa, it will trigger an increase in ventilation.

Question 22

Effects of Hypercapnia

Answer 22

Neurological

• Increased cerebral blood flow
  
  • secondary to vasodilatation and increased mean arterial pressure
  • CBF increases by approximately 7-15 ml/100g/min for each kPa increase in PCO2
  • CBF tends to normalise after prolonged hypercapnia as intracerebral pH is corrected
• CBF tends to normalise after prolonged hypercapnia as intracerebral pH is corrected
  
  • Secondary to vasodilatation
• Narcosis
  
  • Occurs at PCO2> 12 kPa
• Autonomic effects
  
  • Increased circulating catecholamines

Respiratory

• Control of breathing
  
  • mediated by central chemo-receptors in medullar near respiratory centre
  • CO2 rapidly crosses the BBB. In the CSF it dissolves + dissociates to release H+ ions, cannot cross the BBB, pH CSF falls
  • Increasing PCO2 causes a linear increase in minute ventilation
• Pulmonary vasoconstriction
  
  • Alveolar PCO2 > 7 kPa leads to increased pulmonary vascular resistance
• Oxygenation
  
  • O2 dissociation curve shifts to right

Cardiovascular

• Direct effects
  
  • Myocardial: changes in pH impair HR and myocardial contractility. (opposed by increase circulating catecholamines)
  • Blood vessels: Acidosis causes direct arterial vasodilatation (except in the pulmonary vessels where it causes vasoconstriction)
  • Arrhythmia. Acidosis affects intracellular potassium levels in the myocardial conducting tissue, predisposing to rhythm disturbances
• Catecholamine effects
  
  • Myocardial:acidosis causes increase catecholamine release from the adrenal medulla. Increase HR = SV -> increased CO However, in more severe acidotic states the direct effects prevail
  • Blood vessels. In milder acidotic states the circulating catecholamines cause vasoconstriction
  • Arrhythmia. Increased circulating catecholamines cause tachycardia and tachydysrhythmias

Biochemical

• potassium leakage from the cells and an elevated serum potassium.
• shift from ionized to unionized calcium

Question 23

Clinical Signs of Hypercapnia

Answer 23

Respiratory

• Tachypnoea. This will be present unless centrally mediated hypoventilation is the cause of the hypercapnia
• Dyspnoea. Is particularly present where there is a mechanical cause of the hypoventilation, such as airway obstruction

Cardiovascular

• Tachycardia and increased blood pressure result from catecholamine effects
• Reduced peripheral vascular resistance causes flushed skin and bounding pulses

Neurological

• At PaCO2 levels greater than 12 kPa concious level is depressed, ultimately leading to coma
• At lower levels of hypercapnia confusion, muscle twitching and hand flap may be present