Gas Exchange: Hypoxia and Hypo/hypercarbia

Question 1

Define tissue hypoxia?

Answer 1

Describes when the PO2 within the cells is insufficient to allow normal aerobic metabolism to provide energy for cellular functions.

Question 2

What are the types of hypoxia and give clinical examples?

Answer 2

1. Hypoxic hypoxia: low O2 tension (high altitude), hypoventilation, V/Q mismatch (Pneumonia, collapse)
2. Anaemic hypoxia: anaemia, Hb dysfunction (sickle/thalaessemia), reduced oxyhaemaglobin binding (CO binding)
3. Ischaemic/stagnant hypoxia: Lack of oxygen delivery (DO2) due to:
   a) reduced cardiac output
   b) vascular abnormalities (thromboembolism, AV shunting)
4. Histotoxic hypoxia: Oxygen is delivered to cells but unable to be utilised (cyanide poisoning)

Question 3

What are the 3 phases of aerobic metabolism?

Answer 3

ATP is the high energy compound most used for cellular processes and is produced from catabolism of carbs, fat and protein. 3 phases in aerobic metabolism:

Phase 1: Small components of metabolic fuels are initially processed to produce 2 carbon compounds for phase 2 reactions

Phase 2: Citric Acid/Krebs Cycle

Phase 3: Electron Transport chain

Question 4

Describe the different types of Phase 1 reactions?

Answer 4

Glucose can undergo glycolysis to produce 2 pyruvate molecules.

Glucose combines with 2 NAD+ and 2 ATP to produce: 2 Pyruvate 2 NADH2+ and 4 ATP.

Pyruvate then undergoes oxidative decarboxylation to produce 2 Acetyl Coa.

Free fatty acids undergo Beta oxidation to produce Acetyl Coa.

Amino Acids undergo oxidation to produce pyruvate, Acetyl Coa and Kreb cycle intermediates.

Question 5

What are the products of 1 glucose molecule following the Kreb cycle?

Answer 5

Glucose produces 2 pyruvates which are then converted into 2 Acetyl Coa via oxidative decarboxylation.

Acetyl Coa enters the Kreb cycle. It combines with oxaloacetate to produce citrate following which, there are a series of intermediary compounds to produce high energy compounds and carbon dioxide. The last compound produced is oxaloacetate – hence a re-cycle.

For each Gluose molecule there are 2 cycles (as glucose produces 2 x Acetyl Coa)

Each glucose will produce
* 2ATP
* 6 NADH2+
* 2 FADH2
* 4 CO2

Question 6

What happens in Phase 3 of aerobic metabolism?

Answer 6

Electron transfer chain.

Oxidisation of the reduced molecules releases electrons and energy. The energy is utilised for oxidative phosphorylation of ADP to ATP.

NADH2+ enters at the beginning of the chain: converts 3 molecules of ADP
FADH2 enters further down the chain: converts 2 molecules of ADP

**Oxygen is the final electron acceptor in the chain and combines with hydrogen ions to produce water. **Without the presence of oxygen, phase 3 is unable to commence.

Question 7

How many ATP molecules are produced via aerobic metabolism per glucose molecule? (clarify the breakdown)

Answer 7

38 ATPs

Glycolysis: 2 ATP + 2 NADH+ (6 ATP)

Pyruvate to Acetyl Coa: 2 NADH+ (6 ATP)

Kreb’s cycle: 2 ATP + 6 NADH+ (18 ATP) + 2 FADH (4ATP)

Each NADH+ converts 3 ATP and FADH converts 2 ATP

Question 8

What occurs in anaerobic metabolism?

Answer 8

Glucose undergoes glycolysis to produce 2 Pyruvate, 2ATP and 2 NADH+

The electron transfer chain cannot take place as Oxygen is the final electron receiver. As the electron transfer chain cannot NAD and FAD are not reformed so the Kreb’s cycle ceases.

The pyruvate gets converted to lactate (energy is supplied by NADH+ being converted to NAD).

Question 9

How long (time) is your bodies supply of ATP?

Answer 9

90secs

Question 10

At what mitochondrial PO2 level will cells switch to anaerobic respiration?

Answer 10

Once mitochondrial PO2 is less than 0.4kPa.

This is known as Pasteur’s point

Question 11

What happens in cellular hypoxia?

Answer 11

Once the PO2 in the mitochondria drops to <0.4kPa it aerobic metabolism is not possible and anaerobic metabolism takes place which is less efficient.

1. Fall in available ATP: insufficient energy for cell functions i.e. Transport, muscle contraction and enzyme production.
2. Fall in intracellular pH (due to lactate build up) : further inhibition of chemical reactions requiring a narrow pH band

All this results in loss of cell function

Question 12

How does tissue hypoxia affect the following tissues: muscles, neurones and the brain?

Answer 12

Muscle: Failure of production of high energy compounds results in failure of muscle fibre contraction.

Neurones: Ions are unable to move against an electrochemical gradient and therefore, the electrical potential gradient is not maintained and signal propagation ceases

Brain: Cells are most sensitive to hypoxic damage as rely entirely on oxidative phosphorylation of glucose for energy.
* 2 mins = irreversible cell damage
* 4 mins = cell death.

Question 13

4 main effects

What are the early compensatory mechanisms for hypoxia?

Answer 13

1. Changes in Hb/O2 affinity i.e. Bohr Effect
Anaerobic metabolism reduces the pH of tissue and therefore the oxygen dissociation curve shifts to the right allowing easier dissociation of oxygen to tissues.

Within hours 2,3-DPG is produced which has the same effect.

2. Local arteriolar vasodilation which allows better perfusion and delivery.
Stimulated by: ↓PO2 ↓pH ↑PCO2 ↑ local metabolites e.g.adenosine, K+

3. Ventilatory Compensation
Mediated by peripheral chemoreceptors in the Type I cells of the carotid bodies responding to a lower oxygen tension.

It responds to both hypoxia and hypercarbia:
Hypoxia: Has no effect until PaO2 < 7kPa.

Hypercarbia: Linear increase in minute ventilation with increasing PaCO2. This effect is enhanced with hypoxia.

4. Cardiovascular Compensation
Mediated by the peripheral chemoreceptors also from low oxygen tension. Hypotension may also cause this due to stagnant hypoxia and leads to: Vasoconstriction & tachycardia which increases BP and CO resulting in increase tissue perfusion.

Question 14

What are the late compensatory mechanisms to hypoxia?

Answer 14

Occurs with prolonged periods of hypoxia i.e. high altitude, chronic lung disease and anaemia.

This causes an increase erythropoietin production which occurs within hours. However the resulting increase in erythrocytes take 3-5 days and allows an increased oxygen carrying capacity of the blood and hence increased DO2.

Question 15

Describe how increased erythropoietin is produced?

Answer 15

Reduced tissue oxygen availability is sensed by the renal peritubular interstitial cells.

This stimulates increased erythropoietin release (90% from kidneys, 10% liver).

This causes increased differentiation of bone marrow stem cells to procduce RBCs

Question 16

What is the brain’s tissue specific response to hypoxia?

Answer 16

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.

A fall in PO2 below 6.7 kPa leads to exponential increases in CBF from local vasodilation and lactic acidosis production.

Question 17

What is the heart’s tissue specific response to hypoxia?

Answer 17

As coronary oxygen extraction is very high, increases in coronary blood flow is required.

This is achieved through arteriolar dilation from local metabolites, low oxygen tension and myogenic control of arteriolar tone.

Question 18

What are the lung’s tissue specific response to hypoxia?

Answer 18

Hypoxic pulmonary vasoconstriction to balance V/Q ratio.

Locally mediated through inhibition of nitrous oxide production, vasoconstrictor production and direct effect of hypoxia on vascular smooth muscle.

Question 19

Why might end tidal CO2 be lower than PACO2?

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Answer 19

End tidal CO2 may be lower that PACO2 due to mixing with other expired gases.

Question 20

What are the main determinates of PaCO2

Answer 20

1. Alveolar minute ventilation aka removal
2. VCO2 (CO2 production via tissue metabolism) aka production

Question 21

What is the formula for percentage alveolar CO2?

Answer 21

%PAO2= VCO2 (in L) / Alveolar ventilation in L

Of note is that doubling the minute ventiation will halve the %PACO2

Question 22

How can pH be described interms of H+?

Answer 22

pH is the inverse log[H+]

Question 23

What is the henderson hasselbach equation?

Answer 23

pH = pKa + Log [HCO3-]/[CO2]

The implication of the henderson-hasselbach equation is that pH can be maintained by CO2 elimination or by HCO3- / H+ balance in the kidney.

Question 24

What are the causes of hypocapnia?

Answer 24

**Respiratory causes: **
Hyperventilation secondary to hypoxia, pain, anxiety

Compensatory
Hyperventilation as compensatory mechanism if there is a metabolic acidosis

Question 25

What are the causes of hypercapnia?

Answer 25

1.** Increased inspired CO2** from re-breathing or additional exogenous CO2.

2. **Primary respiratory **from hypoventilation or increased dead space
3. Increased CO2 production i.e. in anaesthesia without compensatory rise in mechanical ventilation and in sepsis and malignant hyperthermia
4. Compensatory to a metabolic alkalosis i.e. hypokalaemia, vomiting, additional bicarbonate. This is however limited by the hypoxic effect if PaO2 < 7kPa.

Question 26

What are the effects of hypercapnia on the neurological system?

Answer 26

Increased cerebral blood flow (CBF) secondary to vasodilatation and increased mean arterial pressure. CBF increases by approximately 7-15 ml/100g/min for each kPa increase in PaCO2.

It is most sensitive to blood pH as CBF normalises following prolonged hypercapnia when pH normalises.

The increased vasodilation also causes increased intracranial pressure.

Narcosis occurs – reduced consciousness – usually at levels of PaCO2> 12 kPa and mediated by pH.

Autonomic effects from increasing catecholamines (adrenaline, noradrenaline, dopamine).

Question 27

What are the effects of hypercapnia on the respiratory system?

Answer 27

Increased minute ventilation is mediated through central chemoreceptors located in the medulla close to the respiratory centre. The BBB is more permeable to CO2 and dissolves in the CSF to dissociate into H+ ions which is much slower to move back across the BBB. Therefore, due to the differing permeability of CO2 and H+ it is much more sensitive to a respiratory than metabolic acidosis.

Pulmonary Vasoconstriction occurs with an alveolar PCO2 > 7 kPa and may subsequently alter the V/Q ratio.

Raised alveolar PCO2 may also cause a dilutional alveolar hypoxia which may be compounded by a shift of the Hb/oxygen dissociation curve to the right.

Question 28

What are the effects of hypercapnia on the cardiovascular system?

Answer 28

Direct Effects
* Myocardial contractility is impaired but is usually overwhelmed by increased circulating catecholamines. In severe acidotic states, the direct effects prevail
* Arterial vasodilation caused directly from acidosis causes: flushed skin and bounding pulses
* Arrhythmias may occur due to altering potassium levels in the myocardial conducting tissue.

Catecholamine Effects – induced by acidosis and release from the adrenal medulla
* Myocardial contractility increases from catecholamines.
* Arterial vasoconstriction in milder acidotic states
* Tachyarrhythmias

Question 29

What are the effects of hypercapnia on the biochemical system?

Answer 29

Acidosis from hypercapnia induces potassium leak from cells and an elevated serum potassium.

It also causes: ionised calcium to become unionised