This thing is vaguely pertinent to Section F7(iii) from the 2017 CICM major Syllabus, i m sorry expects the test candidates to it is in able to "explain perfusion-limited and also diffusion-limited carry of gases". Before one can technique that explanation (in another chapter), some basic aspects need to be discussed very first in order for it to make sense. The college had displayed some mild attention in this subject in Question 20 indigenous the first record of 2012 and also Question 22 indigenous the second file of 2016. The examiners" comments to be unusually instructive together to what was expected, and were supplied to fashion this collection of notes.

You are watching: Which of the following indicates the direction of diffusion of gases at the alveoli of the lungs?

In summary:

Diffusion that a gas is a procedure by i beg your pardon a net move of molecule takes ar from a zone in i m sorry the gas exerts a high partial pressure to a region in which the exerts a reduced partial pressure.

Diffusion of respiratory tract gases v the alveolar membrane is determined by

Physical legislations which describe the diffusion of gases v membranes (Fick"s Law and Graham"s law)The capillary transit time the red blood cells.The price of protein-binding reaction (eg. Oxygen-haemoglobin association)

Factors which affect the diffusion that gases in the lung are:

Diffusion coefficient that the gas, i m sorry is influenced by:molecular size (stable and predictable for respiratory tract gases)temperature (stable in many normal human lungs)fluid viscosity/chemical properties of the membrane (altered by disease, eg. Pulmonary fibrosis)density the the gas (insofar together it determinants into Graham"s law) Partial pressure gradient between the capillary and the alveolus, i beg your pardon is affected byAlveolar gas mixtureSolubility that the gas, which impacts the connection of that is partial pressure and also concentrationMixed venous blood gas content Blood-gas barrier thicknessinfluenced by period and disease (eg. Pulmonary fibrosis)Normally about 300 μm Surface area that the pulmonary gas exchange surfaceAlveolar membrane surface ar area Maximum available surface area is around 140m2influenced by period and disease (eg. Emphysema)Capillary surface ar areaMaximum available surface area is approximately 125m2influenced through the level of pulmonary capillary recruitment, pulmonary blood flow and also blood volumeV/Q corresponding describes the interplay in between these factors, together both shunt and dead space result in a lessened gas exchange surface ar area Capillary transit time: Transit time the blood in the alveolar capillaries is normally ~0.75-1.0 secondsA minimum of 0.25 secs is theoretically sufficient to completely oxygenate capillary bloodIn healthy and balanced adults, the minimum capilary transit time is probably around 0.45 secondsWith disease affecting the blood-gas barrier, even a common transit time may be inadequate for enough gas diffusion Protein-gas bindingThe binding of haemoglobin and oxygen has a finite reaction rateThis reaction price is much faster than the diffusion rateDiffusion alone is insuficient to account because that the rate of oxygen absorb in the pulmonary capillariesOther gases (eg. Volatile anaesthetics) also bind to serum proteins and triglycerides 

There is no single reference obtainable which might cover this whole subject matter, various other than the appropriate chapter that textbooks i m sorry CICM candidates have to probably already own. The characteristic function of this topic seems to be the large number that numerical worths which, ~ above closer examination, space not specifically well sustained by references, or which originate in ancient papers indigenous the 1940s. Many textbooks are quite happy come plagiarise from one another and also by part intergenerational cut-and-pasting this values have beentransfer unchanged to the modern-day. The savvy exam candidate is advised come regurgitate these numbers there is no questioning their origin. 

Diffusion in general

Without revisiting content from the chapter pertained to with the motion of substances throughout membranes, it will suffice come restate the definition of passive diffusion from Guyton & Hall (Ch.4):

" kinetic activity of molecules or ions occurs v a membrane opened or through intermolecular spaces without any kind of interaction v carrier protein in the membrane."

That certainly describes the activity of gas molecules across cell boundaries, but is not specifically specific come the setting of respiratory tract gases.  Nunn"s gives an alternative which one might uphold together the definitive statement top top diffusion because that the CICM primary:

"Diffusion of a gas is a process by which a net deliver of molecules takes place from a region in which the gas exerts a high partial press to a zone in which the exerts a reduced partial pressure."

 It is quite quick. One can quantify this quickness using a "permeability coefficient", a measure of just how fast the molecule moves throughout the membrane substance (in systems of distance per second). Gases choose molecular oxygen and also carbon dioxide have great permeability coefficients, and diffuse throughout a lipid bilayer membrane in ~ a rate of 2-3 mm/sec, around one hundred time as conveniently as water. Offered that the blood-gas barrier is approximately 300 nanometres, the first gas molecules across the finish line should record a time of about 0.1 milliseconds.

Diffusion everywhere, consisting of the alveolar membrane, is described by Graham"s law and by Fick"s legislation of diffusion. The last states:

 "The molar flux due to diffusion is proportional come the concentration gradient"

which, in the type of a formula, look at like:


J is "diffusive flux", the magnitude and also direction the the flow of a problem from one compartment to another is the concentration difference dx is the distance for diffusion (or the thickness of the membrane)D is a diffusion coefficient 

...Or, one can sometimes watch it prefer this:


ΔN/Δt is the amount of gas transferred over time is tho the concentration difference dx is still the distance for diffusion (or the thickness that the membrane)A is the surface area of the membraneK is Krogh"s diffusion coefficient, i beg your pardon is usually the diffusion coefficient (D) multiply by the solubility (a) of a gas in the liquid through i m sorry the gas diffuses. 

As one can see, variants ~ above this formula do exist, i beg your pardon is fine, and also CICM trainees who rearrange the formula space unlikely to accomplish with any arguments from the examiners, so long as their expertise of the legislation meets some kind of standards for inner logical consistency. The fundamental things come remember would certainly be:

Diffusion price is proportional to:Diffusion coefficient, or Krogh"s coefficient Partial pressure gradientSurface area that the gas exchange surfaceDiffusion rate is inversely proportional to:Molecule sizeGas densityMembrane thickness

Graham"s Law is often forgotten in the conversation of alveolar gas transfer. It states that the price of diffusion for a gas is inversely proportional to the square source of that is molar mass. In essence, the denser the gas, the slower the diffusion rate. This is perfectly relevant from the approach of a physicist, yet for medication it may be sidelined somewhat, as typically the gases us insufflate our patient with have a fairly predictable density. It"s constantly going to it is in oxygen, or some mix of oxygen and also nitrogen, v occasional fruity-smelling sedative impurities. Sure, top top those rare occasions one could have to give a patience some sort of helium-oxygen mixture, however in those scenarios, one would not ever before be interested in the absorb of the helium into the blood, since though it can get in there, as soon as in over there it go nothing interesting. And of course, in ~ the greater range the densities, there space no representatives whatsoever. As much as the author is aware, over there is no peacetime medical application because that tungsten hexafluoride. In short, CICM test candidates have to be aware of Graham"s legislation for the duration of the exam, and also not beyond.

The factors which affect the diffusion the gases across the alveolar membrane must thus be:

Diffusion coefficient of the gas, i m sorry is influenced by:size that the molecules (predictable, for O2 and CO2)the viscosity the the liquid (probably also quite stable)solution temperature (probably a stable 37ºC)Surface area the the pulmonary gas exchange surface, i m sorry is influenced by:AgeDisease (eg. Emphysema)Degree the pulmonary capillary recruitmentDegree that pulmonary alveolar recruitment (i.e. All determinants which influence atelectasis, consisting of posture, FRC volume, close up door capacity, etc)Partial pressure gradient between the capillary and the alveolus,which is affected by:Alveolar gas mixtureMixed venous blood gas contentHaemoglobin concentrationAffinity that haemoglobin for oxygenSolubility of the gas in water and also lipidBlood-gas obstacle thickness, i beg your pardon is influenced by:AgeDisease (eg. Pulmonary fibrosis)Additionally, capillary transit time (i.e. Term of exposure the blood to the gas exchange surface) is a factor, together the blood in the pulmonary capillaries is constantly moving. 

If one to be to abbreviation this substantial list because that the objectives of an test answer, one can probably (safely) stick to the very first order bullet points. If, however, one to be to litter brevity come the wind, one could proceed reading the rest of this chapter.

Diffusion coefficient of respiratory tract gases

By a fully nonbiologically-centred Fickian definition of this term, the Diffusion Coefficient (D) is a proportionality factor which describes the activity of a massive of substance (over a time interval) through a surface ar of a particular area, follow me a specific concentration gradient. Together such, the is usually represented in terms of square metres or centimetres per second. And judging from that definition, one might concerned the conclusion the it is most likely something quite distinct to every mix of gas molecule and membrane structure. This would be a exactly assumption. Generally, diffusion coefficients space measured experimentally. Factors which affect the diffusion coefficient because that any combination of gas and also membrane include some membrane and medium-specific factors, for example the viscosity the the fluid through i m sorry the gas is diffusing, and also the temperature that the liquid (which around represents the vigourousness of molecule movement; greater temperatures usually lead to quicker diffusion). As one can see, as far as pulmonary physiology is concerned, many of the components which affect gas diffusion are fairly fixed. The temperature of the respiratory structures and also viscosity of the alveolar cytosol is more than likely not going to vary massively from person to person. 

So, what room the diffusion coefficients for respiratory tract gases trying come negotiate the blood-gas barrier? 

Those numbers can look scientific, however the writer soberly confesses that they really space not. Both values come from files which were released as experiment in math modelling the pulmonary gas transfer, wherein the diffusion coefficients were incorporated into the model. Both groups of authors market the same numbers, which appears encouraging, yet neither group offers any type of references as to where they gained them from. In short, the coefficients space quoted below without any experimental data to assistance them. 

What carry out these number mean? Where execute they fit in the grand plan of together numbers, just how do they compare to other diffusion coefficients? Well. To produce contrast, the diffusion of gases through gases could be discussed here, reluctantly, in a temporary excursion away from exam-relevant material. Precious et al (1978) did in reality measure the diffusion coefficients of miscellaneous respiratorily crucial gases together they diffused through various other gases, and also presented their data in the type of a table i beg your pardon is reproduced below for some uncertain education benefit:

If one is somewhat bewildered as to what one should take far from this, that is the the diffusion coefficient for respiratory tract gas mixture varies dramatically from the alveolus (where gas only demands to diffuse through gas) come the physical blood-gas barrier bilayer (where the diffusion coefficient jumps by 5 or 6 orders that magnitude, as viewed in the ar above). 

Surface area of the pulmonary gas exchange surface

The "gas exchange surface ar area" is a relatively elastic parameter which incorporates several factors. One is the crude surface ar area that the alveolar membrane which is accessible for gas to exchange across. The other is the capillary surface ar area, which transforms according come pulmonary blood circulation variation and capillary recruitment. 

Popular folklore holds the the surface of the lungs is around 140m2, or about the exact same area together a tennis court. At any time one look at this figure, that is normally without any type of supporting reference, but digging depth one finds the it is in fact all comes from a 1978 short article by Gehr et al, wherein eight average-sized cadaveric human lungs were resolved in glutaraldehyde and carefully scrutinised using transmission electron microscopy. From these data, Gehr et al concluded the the average lung has an alveolar surface ar area that 143 m2, and a capillary surface ar area of roughly 125 m2. Obviously, every author will report a slightly different number, due to the fact that the surface ar area of the lung is something fairly variable in between different humans, and also even in ~ the same human being over the course of your lifespan. For instance, Sprung et al (2006) uncovered that the full gas exchange surface area decreases indigenous 75 m2 at age 30 come 60 m2 at age 70.

The concentration and also partial pressure gradient

As debated in the chapter on partial pressure and gas solubility, as soon as it concerns the diffusion the gas through solutions, the most vital factor is not concentration but partial pressure. This is due to the fact that different gases have various solubilities in different solvents (water, fat, etc). In a scenario wherein a gas comes into call with 2 solvents where it happens to be much an ext soluble in one, the gas will equilibrate such that the partial push will it is in the same between the 2 solutions, however the gas content (moles every L) will be much higher in the far better solvent. At threat of saturating this website with beaker diagrams:


Observe: though over there is a far-reaching concentration gradient between these 2 compartments, there would certainly be no mass motion of gas due to the fact that the partial pressures room in equilibrium

This nerdy digression aside, the partial push gradients in ~ the alveolar-capillary user interface should usually look something favor this: 


The partial push gradient because that CO2 is a fairly unpredictable thing. Alveolar capillary PCO2 at the start of together a capillary is approximately the very same as the blended venous PCO2, i beg your pardon is around 46 mmHg. Alveolar pCO2 might theoretically it is in the very same as atmospheric (0.3 mmHg in these an overwhelming times), however realistically CO2 invades the alveolus so promptly that the alveolar CO2 is far better described by the alveolar gas equation (PaCO2 × 1.25), and also though it can theoretically be anything, for the diagram 40mmHg to be chosen. The size of the CO2 gradient should therefore it is in close come 6mmHg. The partial push gradient for oxygen is from around 100 mmHg in the alveolus to around 40 mmHg in the capillary, corresponding to the PO2 of mixed venous blood (sats of roughly 75%). Native these miscellaneous statements, one can involved the conclusion that the partial push gradients right here would be influenced by the adhering to factors:

Mixed venous gas contentOxygen exploit ratioMetabolic rateCardiac outputMultiple other possible influencesAlveolar gas mixtureTotal atmospheric pressureFiO2 Alveolar ventilation (i.e even if it is CO2 is being cleared from the alveolus with each breath)

Influence that gas-protein interactions

The life partial pressure gradient is not necessarily the just determinant that gas movement right into the capillary, or the end of it. Take into consideration especially the situation of oxygen:

Oxygen enters right into the capillary blood follow me a partial pressure gradientIn the capillary, the oxygen binds to haemoglobinBound oxygen does not exert a partial pressureThus, partial press dropsThis maintains the partial press gradient in between alveolar gas and also capillary blood, as all the oxygen which has crossed the barrier keeps disappearing into the bottomless haemoglobin sinkhole

Apart from this aspect, one also needs to consider that the plot of binding haemoglobin takes time. This nonzero time interval requirements to it is in factored into the affect of capillary transit time, i m sorry is discussed below. 

Thickness of the blood-gas barrier

In general, if we were to really overanalyse this, there is a substantial and an extremely heterogeneous collection of hurdles which respiratory tract gases should negotiate top top their means to the bloodstream:

Diffusion the one gas v another, in the alveolar gas mixtureDiffusion though aqueous compartmentsAlveolar surfactant waterCytosol that the alveolar lining cells, capillary endothelium and erythrocytesPlasmaDiffusion with lipid compartmentsCell membranesSurfactant layer lipidsDiffusion despite protein layersAlveolar basement membraneProtein materials of surfactant layer and the cell cytosol

To placed it into a sequential order, the barriers to diffusion deserve to be shown in the following manner:


In short, it is a complicated field come cross. There"s in ~ least 5 lipid bilayers and three lakes that cytosol to cross, not to point out a whole ocean the unpredictably swirling plasma. Åberg et al (2010) treat this facility subject with the kind of patient granularity that can potentially drive a human being insane. The CICM trainee most likely does not should know exactly how the cholesterol contents of surfactant influence its gas permeability characteristics. For very first Part exam purposes, it will suffice come say the the barrier consists the multiple moving lipid bilayers, heavy tissue, and water.

The diffusion of gases through gases should be pointed out here, reluctantly, in a short-lived excursion far from exam-relevant material. This takes ar in the airways and also is normally safely ignored. Because that completeness, this apocryphal matter will be included here completely so the trainees have the right to recognise it in the future, and also give the no further thought. Worth et al (1978) did in reality measure the diffusion coefficients of various respiratorily crucial gases as they diffused through various other gases, and also presented your data in the kind of a table i m sorry is reproduced listed below for some uncertain education benefit:

If one is somewhat bewildered regarding what one need to take away from this, that is that the diffusion coefficient for respiratory tract gas mixtures varies dramatically from the alveolus (where gas only demands to diffuse through gas) to the physics blood-gas obstacle bilayer (where the diffusion coefficient jumps by 5 or six orders the magnitude, as watched in the ar above). 

Capillary transit time

Because oxygen and also carbon dioxide do not exchange between the alveolus and capillary instantaneously, the duration spent by blood at the gas exchange surface is clearly an important element of the diffusion process. Each capillary is clearly going to have some individual and different circulation rate and also each erythrocyte will have actually a slightly different transit time, however wherever girlfriend look, friend see civilization quote "0.75 seconds" as the normal time it takes for a red cell to traverse an alveolar capillary.

This figure is repetitive by numerous authoritative voice organs. Specifically, 0.75 secs seems to be really popular through the authors of textbooks. For instance, West"s (p.30 of the 10th edition) and Levitzky (p. 232 the the 7th edition) both provide a transit time of 0.75 seconds, and according to Nunn"s you get 0.8 seconds when you division the total pulmonary capillary blood volume through the total pulmonary blood flow.

Where walk this figure come from? where it appears, there space usually no references, however with a small detective job-related one can determine that the origin of this figure were some early studies which calculated the transit time on the communication of diffusing capacity and also an approximated pulmonary capillary blood volume. This were works by Johnson et al (1960) who obtained 0.79 seconds, or Roughton (1945) who obtained 0.73 seconds. The latter appears to be the very very first time anybody released on this topic: Roughton remarks the "no data, to my knowledge, existed heretofore regarding the size of this physiologically vital yime interval".

Nowadays, the course, we have plenty the data i m sorry is measured straight rather 보다 calculated. For example, one may see a piece of original reseach by Presson et al (1995), that actually did measure capillary transit times in a single subpleural capillary network i beg your pardon they had diverted in the lung the a dog. In-vivo fluorescent videomicroscopy was provided to record and measure the transit times of the RBCs and plasma in the lung (as one aside, one amazing finding from this paper was the red cells were faster than plasma). Across the capillary network there to be a bell-curve circulation of transit times, which to be 3-4 secs on average, with a relaxing heart rate. By enhancing the cardiac output of the dog through isoprenaline, the investigators to be able to decrease both the transit time and also the distribution of times across capillaries, such the all the capillaries became rapid transit capillaries. The initial investigators" data is reproduced here, because honestly there is no much better way to represent the very same information:


This is comparable to the data obtained by Klocke et al (1995), who uncovered a mean transit time of about 1.7 seconds in isolated hare lungs, and Capen et al (1990), who acquired 2.0 secs at rest and 0.8 secs with vigorous exercise. Zavorsky et al (2002) obtained 2.5 secs in a healthy human lung v maximum exercise; Stan Linstedt (1984) gave a figure of 2.0 seconds, v a minimum of roughly 0.5 seconds, and also besides that created a table comparing various measured values among various varieties of mammal.

However, whatever the findings of later studies, many major publications often tend to stick to quoting these numbers from 19945-1960. CICM trainees should probably assume that their examiners will have used those textbooks to produce exam questions and also viva stations. The correct exam answer is thus the 1960s value.

So, that aside, what room the implications of capillary transit time for gas exchange? The answer calls for a quick exploration that the trends of gas diffusion along a capillary. 

Radial and axial diffusion of O2 and CO2

If one to be to consider the pulmonary capillary together a roughly tubular structure, one would mean that there should be two important directions because that gas diffusion. Firstly, there would certainly be the diffusion that the gas into the blood through the wall of the capillary, about along a direction indigenous the perimeter of the capillary towards its centre. Let"s speak to that the "radial" direction for diffusion. Additionally, as blood moves follow me the capillary and also gains (or loses) much more and much more gas, there need to be some adjust in diffusion follow me the longitudinal axis that the capillary. Let"s call this the "axial" direction. 


The direction of greatest interest here will most likely be the axial direction, together this is the adjust in concentration gradient which occurs along the exact same direction as the direction of blood flow. Utilizing a math model, Sharan & sink (1985) to be able to produce this representation of partial pressures follow me the length of an median capillary. Presented below on the same coordinate scale, below one have the right to see a slightly mutated variation of the very same data. The partial pressure numbers describe the PO2 and also PCO2 inside the capillary. The graph only covers the first 20 μm of a capillary, which might be approximately 600 μm long (Staub et al, 1968).


Note the the writer assumed alveolar CO2 will certainly be around 40mmHg, which had actually narrowed that gradient somewhat. Also if they go not, one would certainly be quickly able to conclude that:

CO2 equilibrates with alveolar gas end a really short capillary distanceO2 takes longer to equilibrate with alveolar gasBy the finish of a capillary, the blood is 100% oxygenated

Thus; if the capillary blood is traversing this capillary distance over the supposed average capillary transit time the 0.75 seconds, then after spending about zero secs in the capillary the blood is already completely oxygenated. However, together you rise the capillary transit speed, the capillary transit time shortens. At some stage, girlfriend will fulfill a scenario whereby blood is whistling through the capillaries through such speed that by the end of the capillary those erythrocytes still have actually not had sufficient time to totally oxygenate. Hypoxia will be the result. Moreover, the "slow" capillaries will certainly not be able to compensate because that this hypoxia, as the blood in castle is already maximally oxygenated. 

So, what transit time would certainly be too quick to achieve complete oxygenation that capillary blood? Or, come rephrase the question, how long does that take for capillary blood to accomplish maximum oxygen saturation?

Minimum transit time compelled to oxygenate capillary blood

As one can imagine, no direct measurement of this is available for discussion, yet there are plenty of models. Nunn"s  references Staub (1963), which was a theoretical file using all contemporary data to create predictions that red cabinet oxygen absorb in flowing capillary blood. The steal image, easy Photoshopped, is available below:


As one can see indigenous this relationship, the minimum capillary transit time is about 0.25 seconds (1/3rd that the usual transit time). The other arrows indicate fractions the this usual transit time to show what can happen if capillary transit time to be to decrease. Indigenous this graph, the would show up that, at a transit time of 0.075 seconds (one-tenth that the normal), the erythrocytes would only finish up v a PaO2 of around 80 mmHg, which would still create sats of roughly 96-97%. Conceivably, a transit time i beg your pardon is even much shorter would develop the abovementioned scenario where blood is whooshing through those capillaries so rapid that there is no time for the erythrocytes to choose up any oxygen whatsoever. 

Realistically, exactly how low go transit time go in the real world? In a study which returned plausible and familiar-sounding number, Warren et al (1991) looked in ~ the typical capillary transit time in healthy and balanced athletic humans. Their transit time were about 1.05 secs at rest. V some middle exercise, that value dropped come 0.46 seconds, and also stayed there also as the strongness of the practice increased. The A-a gradients of this athletes raised (not by much - just up come 22.3 mmHg), but the writer were forced to conclude the this might not have actually possibly been the repercussion of a quick capillary transit time.

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However, that"s a group of people who were picked due to the fact that their routine actions included running much more than 64 km cycling over 240 kilometres per week. Points are considerably different if the patient has actually a pathology which decreases the diffusion coefficient of their blood-gas barrier. As they exert themselves and their cardiac calculation increases, the capillary transit time i do not care shortened come the point where hypoxia i do not care a major problem. This has been demonstrated in vivo. Jernudd-Wilhelmsson (1986) concluded the "a limitation on diffusion throughout the alveolar-capillary membrane emerged during exercise, contributing about 30% come P(A-a)O2" in such patients, ~ above the communication of an A-a gradient which had actually doubled regardless of MIGET data which demonstrated a totally unchanged V/Q pattern.

Protein-gas binding rate 

When the capillary transit time was very first being contemplated by the beforehand pioneers, the calculation to identify a rate the oxygen diffusion across the membrane succumbed numbers which were implausibly slow due to the fact that they used simply the raw partial press difference between the alveolus and the capillary, treating capillary blood together a fairly inert recipient fluid (this was the so-called "Bohr integration:, by Christian Bohr, 1911). Of course, it is no inert- the haemoglobin molecules in blood hungrily gobble up every the oxygen molecule as soon as they cross the barrier, and the partial press of oxygen walk not acquire a opportunity to increase until haemoglobin is well-saturated (and the price of the oxygen-haemoglobin reaction diminishes). As soon as you combine the results of this haemoglobin sinkhole, the rate of oxygen uptake into the capillary is enhanced from Bohrian values. Staub et al (1962) discuss this in good detail, and also one particularly illustrative diagram from their article is reproduced below after being misappropriated and also altered:


As one can see, through the oxygen-scavenging results of haemoglobin taken right into account, the diffusion rate is much faster. The test candidate may not have to know about this in any an excellent detail, yet should probably maintain some dim awareness the the truth that the oxygen partial pressure gradient in between the capillary and the alveolus is no the only aspect driving the diffusion. Moreover, some various other gases an in similar way have your alveolar uptake increased by binding to protein or other substances. Great (though contempt veterinary) expedition of anaesthetic medicine solubility by Soares et al (2012) notes the inhaled anaesthetics bind avidly come both albumin and also triglycerides, which would certainly surely affect their uptake from the capillary.