In obstructive lung disease what is happening to the respiratory drive?

[sameeralord]

Hello everyone,

In COPD tell me what I'm thinking is right or wrong.

1. O2 decreases and CO2 increases
2.Central chemoreceptors cause hyperventilation
3. Overtime this is not good enough and CO2 increase, and central chemoreceptors become less sensitive.
4. Peripheral chemoreceptors become the main respiratory drive (driven by decrease in oxygen)
5. So giving oxygen is bad

Now I read somewhere that COPD patients have chronic hypoventilation. I don't understand how they can have hypoventilation, when they must be hyperventilating.

Other thing is I know there are some serious practical problems involved with this. Where people with hypoxic respiratory drive is very rare, and this is an old theoy, and there is pulmonary vasodilation with oxygen, and badly ventilated vessels get more blood flow and thee is a shunt. But I still want to know how respiratory drive case occurs, because then I can understand regulation of respiration.

More questions I have

1. Is alveolar diffusion capacity greater at the apex of lung?

Thanks

 

[thorium1010]

,


Now I read somewhere that COPD patients have chronic hypoventilation. I don't understand how they can have hypoventilation, when they must be hyperventilating.

Other thing is I know there are some serious practical problems involved with this. Where people with hypoxic respiratory drive is very rare, and this is an old theoy, and there is pulmonary vasodilation with oxygen, and badly ventilated vessels get more blood flow and thee is a shunt. But I still want to know how respiratory drive case occurs, because then I can understand regulation of respiration.

:

In COPD there is airflow obstruction, so there is decrease 0xygen and increased carbon dioxide.In normal people the respiratory drive is brought about by the increased carbon dioxide in blood. After a long period the body chemoreceptor loses sensitivity to increased Carbon dioxide (in COPD), which drives the respiratory center .Hence only hypoxia remains for respiratory drive (through peripheral receptors) in COPD pts.

 

[mtc1973]

Alveolar diffusion capacity will be less at the apex because blood flow to the apex of the lung is very small compared to blood flow to the base of the lung. Remember diffusion capacity is based on Ficks law and is a volume of diffusion - not a speed of diffusion.

The best measure of ventilation in a patient is the PaCO2 - the alveolar ventilation equation shows that there is a strong link between alveolar ventilation and PaCO2. So if a patients PaCO2 is high they must have ventilatory problems - in COPD V/Q mismath is the cause. Also not all patients with COPD have hypercapnia (see pink puffer vesus blue bloater) - but they all have hypoxia to some degree. As long as some areas of the lung can ventilate, they can remove CO2 - this is why a patient with only 1 lung (the other with pneumothorax) actually has a low PaCO2. The one remaining lung has a high alveolar ventilation and 'compensates' the CO2. But they always develop hypoxia because of the shunt (the saturation curve of oxygen allows hypoxia to develop - whilst the more linear PCO2 - CO2 content relationship does not let this happen with CO2).

Since COPD is a chronic disease - and usually ends up with some degree of hypercapnia when the majority of the lung has low V/Q ratios - then the PaCO2 is chronically elevated. However, CSF pH is compensated by the choroid plexus and arterial pH is compensated by the kidney. So we now get rid of the elevated respiratory drive at the central chemoreceptors since CSF pH is 'normalized' and normalization of the artrial pH by the kidney also leads to reduced response by the peripherals to the artrial H+ concentration. The only drive left is the hypoxic ventilatory drive by the peripherals.

 

[thorium1010]

Since COPD is a chronic disease - and usually ends up with some degree of hypercapnia when the majority of the lung has low V/Q ratios - then the PaCO2 is chronically elevated. However, CSF pH is compensated by the choroid plexus and arterial pH is compensated by the kidney. So we now get rid of the elevated respiratory drive at the central chemoreceptors since CSF pH is 'normalized' and normalization of the artrial pH by the kidney also leads to reduced response by the peripherals to the artrial H+ concentration. The only drive left is the hypoxic ventilatory drive by the peripherals.

There is a lot of confusion here. how is the csf pH normalised by choroid plexus ? aren't you describing a compensatory mechanism by the body when there is respiratory acidosis.

 

[mtc1973]

Yes - there is respiratory acidosis. A high PaCO2 - in the blood and therefore in the CSF and therefore acidification of both compartments. This is picked up by the central chemoreceptors. But the brain does not like being in an acidic environment - therefore the choroid plexus - that regulates CSF composition - will correct the CSF pH eventually. Now the central chemoreceptors are blind to the elevated PaCO2 since they use CSF pH as an index of CO2 levels.

 

[thorium1010]

Yes - there is respiratory acidosis. A high PaCO2 - in the blood and therefore in the CSF and therefore acidification of both compartments. This is picked up by the central chemoreceptors. But the brain does not like being in an acidic environment - therefore the choroid plexus - that regulates CSF composition - will correct the CSF pH eventually. Now the central chemoreceptors are blind to the elevated PaCO2 since they use CSF pH as an index of CO2 levels.

But the build up of CO2 levels in blood is constant and CO2 can be washed out even in copd by hyperventilation.
what i would like to point out it is reduced sensitivity to high CO2 levels (that is commonly seen in pts with copd) that leads to hypoxia a s a respiratory drive.

 

[sameeralord]

Alveolar diffusion capacity will be less at the apex because blood flow to the apex of the lung is very small compared to blood flow to the base of the lung. Remember diffusion capacity is based on Ficks law and is a volume of diffusion - not a speed of diffusion.
.

Hey thanks for the answer. However I don't understand, how flow rate can affect diffusion limited substances. I mean if a substance is flow limited I can understand. Also does hypoventilation occur in COPD? How does that happen. Also do peripheral chemoreceptors sensitive to increases or decreases of carbon dioxide. One book said increase other said decrease.

 

[mtc1973]

Thorium - what is the mechanism of reduced sensitivity? That is the question. Part of the reduced sensitivity is because of compensation of the CSF pH!

So with COPD (with those patients that do have hypercapnia) - PaCO2 levels are high - chronically - CO2 leads to bicarb and H+ production. Leading to respiratory acidosis - so high H+ in blood and CSF. So initially there is respiratory drive from the central (because of H+ in CSF) and peripheral (because of hypoxia and H+ arterial). Now as the kidney compensates H+ in the blood - we loose drive from peripheral chemoreceptors in response to arterial H+, as CSF pH is corrected we loose drive from central receptors detecting H+ (produced by CO2). We now only have respiratory drive from the peripheral in response to hypoxia (under steady state conditions).

 

[mtc1973]

samealord - diffusion capacity is affected by blood flow - even a diffusion limited gas (in fact we use CO to measure diffusion capacity - because it is a diffusion limited gas). Again it is not the rate of equilibration of partial pressure you are measuring with diffusion capacity (like DLCO test) - it is the total VOLUME that has diffused across the gas exchange surface and into the blood you are measuring. Again - Ficks law - do not confuse diffusion capacity with rate of diffusion and hence rate of equilibration of partial pressure.

Central firing rate is determined by CSF pH - increase pH and reduce firing rate = slow ventilation. Decrease pH and increase firing rate and speed ventilation. Central chemoreceptors do NOT detect PCO2 directly - they detect H+ - and usually the PCO2 is directly related to CSF pH because H2O + CO2 ---- H+ and HCO3- - raise CO2 - make more H+ - lower CO2 - make less H+.

So a diffusion capacity test is not measuring if a substance is perfusion or diffusion limited. It is measuring volume that diffuses - e.g. in diseases like emphysema - the rate of diffusion is not affected in terms of partial pressure equilibration but the diffusion capacity is reduced because there is less surface area and hence less volume diffusing across. If a gas is diffusion limited is simply means that the alveolar partial pressure does not equilibrate with the capillary partial pressure. IF the partial pressure does equiilibrate then it is said to be perfusion limited.

 

[sameeralord]

samealord - diffusion capacity is affected by blood flow - even a diffusion limited gas. Again it is not the rate of equilibration of partial pressure you are measuring with diffusion capacity (like DLCO test) - it is the total VOLUME that has diffused across the gas exchange surface and into the blood you are measuring. Again - Ficks law - do not confuse diffusion capacity with rate of diffusion and hence rate of equilibration of partial pressure.

Central firing rate is determined by CSF pH - increase pH and reduce firing rate = slow ventilation. Decrease pH and increase firing rate and speed ventilation. Central chemoreceptors do NOT detect PCO2 directly - they detect H+ - and usually the PCO2 is directly related to CSF pH because H2O + CO2 ---- H+ and HCO3- - raise CO2 - make more H+ - lower CO2 - make less H+.

So a diffusion capacity test is not measuring if a substance is perfusion or diffusion limited. It is measuring volume that diffuses - e.g. in diseases like emphysema - the rate of diffusion is not affected in terms of partial pressure equilibration but the diffusion capacity is reduced because there is less surface area and hence less volume diffusing across. If a gas is diffusion limited is simply means that the alveolar partial pressure does not equilibrate with the capillary partial pressure. IF the partial pressure does equiilibrate then it is said to be perfusion limited.

Hey thanks mtc1973 that was a major misunderstanding I had. So is alveolar diffusion capacity, directly proportional to its partial pressure. If its partial pressure is higher, it can diffuse over a large area so must be true right.

 

[mtc1973]

not sure what you mean here?
Here is how we measure diffusion capacity in a patient. Get them to breath in a very low concentration of carbon monoxide (also helium - but let's forget that part though). Now we know the partial pressure of CO in the alveolus because we provide it. We also know the partial pressure in the blood = zero. Because as soon as CO passes into blood it binds Hb and has no effect on partial pressure. So we know know the gradient - the alveolar at whatever we provide (P1 = PACO) and the blood at zero (P2 = PaCO). ((So this is why we choose CO - because without measuring blood we know that for a low PACO the blood PaCO is zero - if we choose a perfusion limited gas we cannot make this prediction))

Ficks law is that

volume of CO VCO = area/thickness*diffusivity * (P1 - P2)

we bunch area/thickness*diffusivity to a common term DL (diffusion capacity).
And rearrange to get

DL = VCO/PACO

we know PACO as we are providing it and we know VCO uptake as we measure the exhaled CO volume and compare it to exhaled - so now we have a value for the DL - a combined term for the area/thickness and diffusivity. The diffusion capacity.


So now you see why blood flow matters - without blood flow less CO would make it into the blood! The capacity for CO to diffuse would be less because we would not have fresh blood for CO to move into. Therefore all the CO you breathed in - would be breathed back out (more or less) and your DLCO would be zero. (A hypothetical man with ventilation and no perfusion...hmm)

Clinically a value of 25 ml CO min-1 mmHg is okay - any less than this and you have a low diffusion capacity. Maybe diffusion is slow e.g. fibrosis, maybe area is low like emphysema or low because blood flow is low like chronic heart failure.

 

[sameeralord]

not sure what you mean here?
Here is how we measure diffusion capacity in a patient. Get them to breath in a very low concentration of carbon monoxide (also helium - but let's forget that part though). Now we know the partial pressure of CO in the alveolus because we provide it. We also know the partial pressure in the blood = zero. Because as soon as CO passes into blood it binds Hb and has no effect on partial pressure. So we know know the gradient - the alveolar at whatever we provide (P1 = PACO) and the blood at zero (P2 = PaCO). ((So this is why we choose CO - because without measuring blood we know that for a low PACO the blood PaCO is zero - if we choose a perfusion limited gas we cannot make this prediction))

Ficks law is that

volume of diffusion VCO = area/thickness*diffusivity * (P1 - P2)

we bunch area/thickness*diffusivity to a common term DL (diffusion capacity).
And rearrange to get

DL = VCO/PACO

we know PACO as we are providing it and we know VCO as we measure the exhaled CO volume - so now we have a value for the DL - a combined term for the area/thickness and diffusivity. The diffusion capacity.

According to the equation if the partial pressure gradient increases , diffusion capacity decreases. Why is that ? If gradient increases more should diffuse right?

EDIT: Or wait I think I have jumbled this all up. Is diffusion capacity, simply as you have said, area/thickness or surface area it has nothing to do with partial pressure! I think I undersand now.

 

[mtc1973]

Well if you increase the driving gradient - you will increase the volume taken up by the lungs so DLCO should remain (over sensible physiological/clinical ranges) normal.

So increase bottom term will result in an increase of top term and the same DLCO.

 

[bobze]

According to the equation if the partial pressure gradient increases , diffusion capacity decreases. Why is that ? If gradient increases more should diffuse right?

EDIT: Or wait I think I have jumbled this all up. Is diffusion capacity, simply as you have said, area/thickness or surface area it has nothing to do with partial pressure! I think I undersand now.

No it has to do with partial pressure gradient;

V_gas= (surface area*solubility*(P₁-P₂))/ thickness*√molecular weight of gas

**note V here is a flow rate

Under normal physiological conditions though, the P gradient of CO2 should be pretty close to 0 (45/6ish in PA vs 40 in venous blood). CO2 normally equilibrates across the alveolar membrane and normally perfusion limited.

Under pathophysiological conditions that results in an reduced diffusion capacity CO2 becomes diffusion limited (ie; even increasing the perfusion still doesn't allow CO2 to eqilibriate)

 

[mtc1973]

Partial pressure gradient of carbon monoxide is used to measure diffusion capacity clinically, not CO2.

The partial pressure gradient of CO2 is about 5-6 mm Hg not zero otherwise we wouldn't get gas exchange - and venous blood is 45-46ish and alveolar 40ish (other way round to how you put it..)..

Partial pressure of CO in blood is zero because once CO crosses into the blood it binds to hemoglobin and does not exert a partial pressure (using low PACO). This is why its such a useful gas for this test.

Its hard to do this test accurately with CO2 or oxygen as you have to measure both alveolar and blood gas levels - but acurate blood gas levels at the pulmonary capillary are impossible clinically. Blood tests are arterial blood - where the gases do not fully represent what has taken place in the pulmonary capillary.

Remember also - Vgas is the volume of uptake in ml min, DLCO (the diffusion capacity) - is the uptake in ml min per mm Hg gradient.

 

[thorium1010]

Thorium - what is the mechanism of reduced sensitivity? That is the question. Part of the reduced sensitivity is because of compensation of the CSF pH!

So with COPD (with those patients that do have hypercapnia) - PaCO2 levels are high - chronically - CO2 leads to bicarb and H+ production. Leading to respiratory acidosis - so high H+ in blood and CSF. So initially there is respiratory drive from the central (because of H+ in CSF) and peripheral (because of hypoxia and H+ arterial). Now as the kidney compensates H+ in the blood - we loose drive from peripheral chemoreceptors in response to arterial H+, as CSF pH is corrected we loose drive from central receptors detecting H+ (produced by CO2). We now only have respiratory drive from the peripheral in response to hypoxia (under steady state conditions).

you do realize pa CO2 in copd pts are constantly elevated despite the compensation by the kidney in form of loss of hydrogen ions. And CO2 levels never comes down to normal i.e. copd pts have hypercapnia despite renal compensation.

 

[mtc1973]

Yes - Kidney compensates H+ - so what are you meaning here? OF course CO2 is elevated - because there is a ventilatory problem - a large V/Q mismatch. That has nothing to do with what I stated!?

Thorium - central chemoreceptors do not sense the partial pressure of carbon dioxide. They sense H+ ions. Normally H+ ions are a good index of CO2.

Thorium - what exactly is your point?

 

[thorium1010]

my point was that despite compensation by the kidney co 2 is constantly elevated. Then CO2 should also be a driver of the respiratory centre or respiratory drive (since CO2 levels never reach normal levels in COPD pts)

 

[mtc1973]

Constantly elevated CO2 means more H+ ions in the CSF - which is then corrected.

Most literature indicates that H+ ions are sensed not PCO2! But that PCO2 and H+ ion concentrations are related. However, with COPD the high PCO2 is not 'seen' by the central chemoreceptors since the CSF pH is corrected! I don't know how to say this any other way!

Author(s): Chernov MM (Chernov, Mykyta M.)1, Erlichman JS (Erlichman, Joseph S.)2, Leiter JC (Leiter, J. C.)1
Source: RESPIRATORY PHYSIOLOGY & NEUROBIOLOGY Volume: 173 Issue: 3 Special Issue: Sp. Iss. SI Pages: 298-304 Published: OCT 31 2010
Times Cited: 0 References: 52 Citation Map
Abstract: A comparative analysis of chemosensory systems in invertebrates and vertebrates reveals that different animals use similar strategies when sensing CO2 to control respiration. A variety of animals possesses neurons that respond to changes in pH. These respiratory chemoreceptor neurons seem to rely largely on pH-dependent inhibition of potassium channels, but the channels do not appear to be uniquely adapted to detect pH. The 'chemosensory' potassium channels identified thus far are widely distributed, common potassium channels. The pH-sensitivity is a common feature of the channels whether the channels are in chemosensory neurons or not. Thus, the pattern of synaptic connectivity and the mix of potassium channels expressed seem to determine whether a neuron is chemosensory or not, rather than any special adaptation of a channel for pH-sensitivity. Moreover, there are often multiple pH-sensitive channels in each chemosensory neuron. These ionic mechanisms may, however, be only part of the chemosensory process, and pH-dependent modulation of synaptic activity seems to contribute to central chemosensitivity as well. In addition, the exploration of the mechanisms of pH-dependent modulation of ion channel activity in chemosensory cells is incomplete: additional mechanisms of pH modulation of channel activity may be found, and addition conductances, other than potassium channels, may participate in the chemosensory process. (C) 2010 Elsevier B.V. All rights reserved.

 

[mtc1973]

OKay - let's try again. We agree that PCO2 is elevated.
This leads to respiratory acidosis - H+ in blood and H+ in CSF.

H2O + CO2 ------ H+ + HCO3-

so as CO2 increases on the left - more H+ is produced on the right. This happens in blood and CSF. So CO2 is related to pH - higher chronically elevated PCO2 leads to chronically more H+ ions in blood and CSF. At this point the low pH of CSF - causes blocking of K channels on the central chemoreceptors and depolarization - and signals are sent to the respiratory centers to speed up ventilation - and reduce PCO2 - and hence CSF H+ ion concentration.
In chronic disease however - the brain does not like to be in a low pH environment - and therefore homeostatic mechanisms kick into correct pH. So now we have chronically elevated PCO2 in the CSF - but normal H+ ion concentration (the choroid plexus is normalizing CSF pH). So now although the PCO2 is high - the central chemoreceptors do not know this because pH is normal - i.e. CO2 levels and H+ in the CSF have become uncoupled. Now we have high CO2 and normal CSF pH and so the central chemoreceptors that sense CSF pH - are unaware that the PCO2 is high. And so there is no additional respiratory drive from the centrals - as they think PCO2 is normal.

The central point here is that normally the central chemoreceptors use H+ as an index of PCO2. In chronic disease H+ is an unreliable index of PCO2 because other compensatory mechanisms change the CSF pH and uncouple the relationship between PCO2 and H+.

 

[mtc1973]

Diagram may help.

 

[thorium1010]

ok maybe i was not clear enough before, i did not disagree with mechanism H+ ions in csf or that renal compensation is not important. All i wanted to point out was that the co 2 levels were constantly elevated in copd pts and over time a kind of reduced sensitivity occurs in these pts. It has been found despite the high CO2 levels the csf pH in these pts remains normal- compensation by renal mechanism is important, but this alone is not sufficient another proposed mechanism is the high bicarbonate concentration in csf. Over time increase in CO2 levels does not change CSF pH - so yes this is a kind of desensitization even though at the same time if arterial pH is measured it would gone down (more acidic).

 

[mtc1973]

renal compensation corrects arterial pH
the choroid plexus compensates CSF pH

choroid plexus compensates pH either by getting rid of H+ or by raising HCO3 and buffering H+

either way - elavated CO2 is no longer sensed because PCO2 and H+ are uncoupled.

The reduced sensitivity to PCO2 is becuase the pH is corrected to near normal levels - and hence ventilatory output is back to near normal levels (from the centrals).

So I guess we are on the same page now. :)

 

[thorium1010]

mtc1973,

yeah i agree with everything in your post.

So I guess we are on the same page now. :)

yep

 

[bobze]

Partial pressure gradient of carbon monoxide is used to measure diffusion capacity clinically, not CO2.

The partial pressure gradient of CO2 is about 5-6 mm Hg not zero otherwise we wouldn't get gas exchange - and venous blood is 45-46ish and alveolar 40ish (other way round to how you put it..)..

Partial pressure of CO in blood is zero because once CO crosses into the blood it binds to hemoglobin and does not exert a partial pressure (using low PACO). This is why its such a useful gas for this test.

Its hard to do this test accurately with CO2 or oxygen as you have to measure both alveolar and blood gas levels - but acurate blood gas levels at the pulmonary capillary are impossible clinically. Blood tests are arterial blood - where the gases do not fully represent what has taken place in the pulmonary capillary.

Remember also - Vgas is the volume of uptake in ml min, DLCO (the diffusion capacity) - is the uptake in ml min per mm Hg gradient.

You're right I did write that backwards, sorry it was "early" in the morning for me . I know the gradient is actually zero, hence my pointing out the numbers that a gradient does exist.

The point I was making is that for some gases (like CO2) the partial pressure gradient is a less important determinant for rate of diffusion than others (like the solubility of CO2 under physiological conditions).

It was a reply specifically to; "area/thickness or surface area it has nothing to do with partial pressure!"

Yes I also know that CO is used to measure clinically, .03% or something thereabouts. I wasn't suggesting that CO2 is used. That's a good point you make about CO though, for someone trying to understand why we use it to measure. Because CO has about a 200 times greater binding affinity for Hb than does oxygen, it means CO is a diffusion limited gas--Making it a good candidate for this type of calculation.

 

[mtc1973]

my bad bob - no worries

 

[bobze]

my bad bob - no worries

No problem, I was pretty groggy when I wrote that (up till 4 the night before re-watching renal physiology lectures )--Rereading it I wasn't very clear lol.

 

[mtc1973]

there's a lot more like you tonight - our physiology exam is on thursday!

 

[bobze]

there's a lot more like you tonight - our physiology exam is on thursday!

!! Ours isn't till next wed. Which is good I guess, and we only had 3 classes this block, but I think because of that each course director made their stuff harder assuming we all had all this "extra" time laying about, LOL

 

[mtc1973]

Good luck! What course text do you use?