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B. 5 Diffusive transfer of respiratory gases a. Describe and explain the oxygen cascade. The partial pressure of oxygen falls at each stage of its transport from air to peripheral tissues. Dry air Air at BTPS Alveolar gas Pulmonary capillary blood Mean capillary blood Interstitial fluid Intracellular fluid 159 mmHg 149 mmHg 100 mmHg 40 → <100 mmHg 40 mmHg 15-40 mmHg ≥1 mmHg for normal metabolism The fall from dry to saturated air results from the increase in the partial pressure of water from 0 to 47 mmHg. The pressure in inspired gas also depends upon barometric pressure. The difference between inspired gas and ideal alveolar gas depends on ventilation and oxygen useage. With high alveolar ventilation, alveolar PO2 approaches inspired PO2 asymptotically. Alveolar PO2 is also reduced by oxygen uptake and CO2 release in the alveoli. The gradient between alveolar gas and pulmonary capillary blood depends on the factors affecting diffusion described below. In addition it is increased by shunt and V/Q scatter. A high inspired PO2 increases the pressure gradient because the content gradient remains constant while the content/pressure graph becomes very flat at high PO2. A fall in cardiac output causes a rise in the proportion of shunted blood as well as a fall in mixed venous PO2 due to constant tissue oxygen uptake. A very marked rise in cardiac output can also increase the A-a gradient by reducing transit time in the pulmonary capillaries to the extent that oxygen uptake becomes diffusion-limited. Factors which influence the shape of the oxygen dissociation curve also affect A-a gradient: pH, temperature, and 2,3-DPG. An increase in haemoglobin concentration also reduces A-a gradient. An increase in ventilation can cause a rise in A-a gradient both due to the rise in alveolar PO2 and the fall in cardiac output which accompanies the fall in PCO2. If there is more than 3% shunt, increasing ventilation starts to cause a fall in arterial PO2 because of the fall in cardiac output. The gradient from blood to interstitial fluid to intracellular fluid differs markedly from tissue to tissue and regionally within any tissue. It is dependent on perfusion, haemoglobin concentration and oxygenation of blood. In most tissues passive diffusion carries oxygen down the concentration gradient from capillary blood to the mitochondria. Some tissues such as muscle have specialized oxygen carrying proteins (myoglobin) to improve oxygen transport and storage. b. Explain the capillary exchange of oxygen and carbon dioxide, and the relationship of erythrocyte transit to oxygen and carbon dioxide transfer. 100 Respiratory diffusion 1.B.5.1 PO2 (mmHg) O2 and CO2 cross the blood-gas barrier by passive diffusion. The distance from alveolar lumen to erythrocyte cytoplasm is about 0.3 µm. O2 diffuses rapidly across this barrier, equilibrating with blood in about 0.25 s. At rest, erythrocyte transit time in alveolar capillaries is about 0.75 s, however in exercise it falls to as little as 0.25 s. The time taken for diffusion can be greatly increased by lung disease which results in Normal Diseased 50 0 .25 .5 Time (s) .75 James Mitchell (December 24, 2003) thickening of the blood-gas barrier and consequent diffusion-limitation of oxygen transport. A reduction in the pressure gradient driving diffusion will also slow diffusion. This is seen at high altitude, where PAO2 is reduced by a greater amount than the fall in venous PO2. CO2 is much more soluble than O2, however the pressure gradient driving its diffusion is only 5 mmHg. In healthy lungs the time taken for alveolar gas to equilibrate with pulmonary capillary blood is about the same as with O2: 0.25 s. c. Explain perfusion-limited and diffusion-limited transfer of gases. In gas exchange at the blood-gas barrier, the rate-limiting step differs according to the gas being examined. In the case of oxygen, as described above, the partial pressure equilibrates in much less time than the blood spends in alveolar capillaries. Thus transport of oxygen is limited by the total alveolar blood flow at rest; it is perfusion-limited. N2O is an extreme case of perfusion-limitation as it reaches equilibrium with blood in around 0.1 s. Perfusion-limitation is a characteristic of gases and anaesthetic vapours which are roughly equally soluble in the blood-gas barrier and in blood. In exercise, when the transit time for blood is reduced substantially and if the diffusion capacity for oxygen is reduced by lung disease, the partial pressure of oxygen in pulmonary venous blood may still be much lower than in alveolar gas. CO diffuses much less readily than O2, with a very gradual rise in blood partial pressure. Its transport is thus almost entirely dependent on the rate of diffusion through the blood-gas barrier, hence its use in measuring diffusion capacity. This is a case of diffusion-limited gas transport and is characteristic of gases which have widely differing solubilities in the blood-gas barrier and in blood. d. Define diffusion capacity and its measurement. Diffusion capacity is a measure of the rate at which a gas can diffuse across the blood-gas barrier. It is described by Fick’s law of diffusion. The rate of diffusion is proportional to the area (A) and pressure gradient and inversely proportional to the thickness (T) of the sheet. It is proportional to the diffusion constant which is equal to the solubility of the gas (Sol) divided by the square root of its molecular weight (MW): ˙ ∝ A ⋅Sol(P1 − P2 ) V gas T MW Because area and thickness of the blood-gas barrier are not readily measurable, an empirical “diffusing capacity” for each gas is defined such that: ˙ = D ⋅ (P − P ) V gas L 1 2 where DL is the diffusion capacity for the gas being tested. In the case of O2 and CO, uptake is also limited by reaction with haemoglobin. This is also included in DL. DL can then be split into two components, with DM representing the conductance of the blood-gas membrane, VC the capillary blood volume, and θ representing the rate of reaction with Hb (in ml/min/ml blood/mmHg): 1 1 1 = + D L D M θ ⋅ VC Diffusion capacity is conventionally measured using CO as its transport across the blood-gas barrier is diffusion-limited and its normal blood concentration is nearly zero. This can be done with a 10s single breath-hold of a 0.3% CO and 10% He containing mixture to measure both lung volume and DLCO or using a steady-state technique with measurement of CO uptake over several breaths. At rest DLCO is typically 25 ml/min/mmHg. With exercise it increases by a factor of three or more due to pulmonary vasodilatation and alveolar recruitment. e. Describe the physiological factors that alter diffusion capacity. Increase Respiratory diffusion 1.B.5.2 James Mitchell (December 24, 2003) blood-gas barrier area lung size alveolar recruitment alveolar gas concentration pulmonary vasodilatation uptake of CO or O2 by Hb or buffering of CO2 Decrease blood-gas barrier thickness systemic venous blood gas concentration temperature (reduces solubility) functional dead space Respiratory diffusion 1.B.5.3 James Mitchell (December 24, 2003)