I'll be talking about the studies that ourselves and others have been engaged in that suggests
that CO2 is probably, although it's a waste molecule, is a good molecule.
I'll start and finish this presentation by saying these are preclinical or preliminary
studies.
These are not recipes for practice.
In terms of targeting CO2, we have a long literature, a long history of measuring blood
gases and responding to them.
And when we wonder, how did we get here?
Well, this is a case report from the 1990s.
It's a characteristic of many such case reports whereby Adnet and colleagues, working with
Didier Payen described prolonged severe hypercapnia complicating near fatal asthma in a 35-year-old
woman.
And many of us would have managed patients something like this whereby you simply are
unable to ventilate a patient.
Their PA CO2 is extreme.
By any standards, a PA CO2 over 200 is extreme with profound respiratory acidosis.
And what do you do?
Well, if you're young and very keen, you might try and try and try and ventilate that patient.
But if you try to do that with extreme ventilatory maneuvers, very high pressures or tidal volumes,
what you will end up doing, of course, is shredding the lungs.
If you can bronchodilate the patient or wait until the patient's disease abates, as happened
here, then the outcome will likely be a whole lot better.
It was in pediatrics and neonatology.
[INAUDIBLE] said her husband is a neonatologist.
Well, JT Wung is a neonatal practitioner and an anesthesiologist in Columbia University
in New York.
And what he described was what was subsequently described as permissive hypercapnia by Hickling
and colleagues in adult ARDS.
And what JT Wung did was completely revolutionize not with an RCT, but with an observational
study, a small number of kids who had persistent pulmonary hypertension of the newborn.
And the standard therapy there in order to try to reduce the PVR, which of course is
a real inherent problem in that condition, was to hyperventilate with extreme measures.
And he reckoned that, in fact, caused physical damage to the lungs and he backed off.
And he used non-invasive ventilation just as a support.
And was able to describe far better outcomes in a cohort.
Keith Hickling, in a retrospective and then a prospective controlled study, was able to
demonstrate the same with patients whom he thought had adult ARDS.
John Laffey, a colleague of mine, wrote this schematic in an article he wrote for The Lancet
in 1999 where he described traditional therapy is really based in the operating room.
Traditional ventilation, whereby the tidal volume was high.
The carbon dioxide was considered to be a bad gas, and the lower the better.
Certainly, it should be normal.
But the outcome subsequently was realized was the potential for lung injury, particularly
if the lungs were injured to start with.
And in this context, there may, in fact, be systemic injury.
With Keith Hickling and the idea of permissive hypercapnia, the notion became accepted that
the high stretch was bad and you should target low stretch.
If you do that, of course, there's only so much you can increase the minute ventilation.
The CO2 will be high.
It was never thought at that stage that the high CO2 of itself was a benefit.
It was thought that it was probably not good, but it could be tolerated.
And the CO2 was a bystander.
And the outcome was reduced lung injury because of the low mechanical stretch.
The idea then of therapeutic hypercapnia-- probably a premature word because it implies
that you might use it on patients.
We would not recommend at this stage that you use this as a therapy on patients.
But of itself, it says that CO2 can, under certain circumstances, be protective, independent
of the amount of ventilation.
And so when you deliberately elevate CO2, you can also reduce lung injury and also reduce
systemic injury.
And this is the article that John wrote, which is an example of a completely biased review.
Everybody these days wants balanced reviews.
We've no interest in a balanced review.
We wanted to get the point of view across.
And so in a characteristic style, we listed every possible benefit of CO2 and omitted
every possible harm just so you understand one side of the argument very, very clearly.
I know that's not very polite, but it's the only way to get your point of view across.
And what you can see is there are a large number of ways that hypercapnia can be anti-inflammatory.
There are a large number of ways on a global and on a micro-circulation level whereby we
know that oxygen delivery was increased with hypercapnia.
And consumption, because the cellular metabolism is suppressed, is reduced.
So the O2 supply-demand balance is favorably impacted.
Well, does it work?
Well, Kazue Shibata, who worked with us several years ago, studied this in a rabbit lung.
Now, we don't treat rabbits and we sure don't treat isolated rabbit lungs.
So you got to be a little careful about generalizing this.
But if you happen to be treating a rabbit lung in your ICU and you subject the rabbit
lung to ischemia and reperfusion, you will get leaky lungs like what you get with reperfusion.
And here's the model.
Here is the leakiness, the KF from the starting equation.
And here is normal capnia before and after reperfusion.
And after reperfusion-- this is by design-- there's a big increase in the leakiness of
that lung.
But if you did reperfusion in the context of a very high-- and that would be a very,
very high level of CO2, 25% CO2-- there's a big, big drop in the amount of damage.
The ventilation is the same.
What we controlled here separately is added CO2 to the inspired gas.
So far, that seems pretty good.
So John Laffey then took up this and studied in rats.
And he didn't just look at the lung.
He looked at the whole animal.
So this is the anesthetized rat who has an operation, a laparotomy.
And the mesentry is made ischemic and then reperfused.
So it's much more relevant to a critical care scenario.
Of course, it is not an ICU patient scenario, but it's more relevant to it.
And what you can see here is the lung leakage.
Evans Blue leakage in the BAL fluid after reperfusion of the mesenteric artery.
And if you add no extra CO2 to the inspired gas, such as what we usually do, you get a
certain amount of injury.
And the more CO2 you add to the gas, the less injury that you get.
And you say, well, that's very cool.
Right up to 10% CO2, which gives you a CO2 of right about in the high 90s.
What the editors didn't allow us to publish here was the animals that are over here.
And they were animals with 20% CO2.
And all of those animals had perfect lungs, but unfortunately 80% of them were dead.
So you might say, well, that's a bit of a problem.
It's not really a problem.
It makes it biologically plausible.
There is no therapy that we know of where more is better ad infinitum.
So there's something beneficial, at least to the lungs, in this model in the modest
range of added CO2.
You can see here therapeutic hypercapnia prevents chronic hypoxia induced pulmonary hypertension.
Here, you can see that when animals versus controls are subject to low oxygen levels,
what you can see is an increase in the right ventricular hypertrophy.
And if they're growing up exposed to 5% CO2 or 10% CO2, the amount of hypertrophy they
develop is a lot less.
And you might say well, hang on a second.
Doesn't hypercapnia augment-- make worse-- hypoxic pulmonary vasoconstriction?
Yes, it does acutely.
Chronically, it seems to, in fact, reduce it.
So this could be an important issue, potentially.
And what you can see, in fact, is how that works where you have preproendothelin which
is the precursor of endothelin.
That is, the pulmonary vasoconstrictor.
I beg your pardon.
In hypoxia, with no CO2, there's a lot of endothelin precursor and a lot less when CO2
is added.
A very important question is what happens in infection because much of the patients'
problems that we look after involves infection.
They come in with infection or they acquire infection.
And so [INAUDIBLE] working with John Laffey in Galway in Ireland looked at a short term
model of acute infection.
And what you could see here is that the ratio of airspace to tissue is adverse in the context
of normal capnia.
And in the context of hypercapnic acidosis, there's less tissue and more airspace.
And that means the lungs are less congested and there's less inflammation.
And so in this context, hypercapnia seems to be good if you're looking after a rat who
has a six hour history of pneumonia.
But if you're looking at a much more realistic model, you can see a two-day model here of
E. coli and pneumonia.
And what you can see here is that in the context of CO2, with E. coli it's not better compared
with baseline.
It actually seems to be worse.
And when they took samples of the lung and did a colony count for E. coli, they saw that
with hypercapnia, over days there's more bugs.
Well, how could that be?
Well, it looks like it's not good.
And why is that the case?
They looked at the neutrophil function.
Neutrophils, very bad when they're overactive but very necessary when you're trying to clear
E. coli.
And, in fact, the neutrophils are hypo-active, allowing proliferation of the E. coli and
worsening of the clinical context.
In the context of ventilator induced lung injury, just pure stretch induced lung injury,
things are better.
With low tidal volume, the elastins doesn't really change.
With high tidal volume, the elastins increases.
Elastins is the reciprocal of compliance, and therefore higher values are bad.
But high tidal volume in the context of CO2, you still get injury but a lot less so.
So what you can see here is it kind of depends on the model.
There is no way that high CO2 is good for everything.
It's clearly bad for some things and good for other things.
Could it be beneficial to patients?
Well, Mariani showed here with permissive hypercapnia that the time left on mechanical
ventilation was, in fact, a lot shorter.
Maybe good.
David [INAUDIBLE] did a retrospective review of the ARDS database and suggested that for
patients in the high tidal volume group that the presence of hypercapnic acidosis was protective.
It's protecting them against ventilator-induced lung injury, just like our mice.
But in the patients with a low tidal volume who are not getting ventilator-induced lung
injury, it made no difference.
Does the brain matter in this context?
It does.
If you're exposed to high CO2's, then you withdraw CO2 or expose the patient to low
CO2, what you will get is cerebral vasoconstriction.
Cerebral vasodilation may be good in some contexts.
Cerebral vasoconstriction can be very good in some contexts, too.
If you're about to die from cerebral herniation, then you want to have cerebral vasoconstriction.
But if you're not about to die from herniation, cerebral vasoconstriction is probably bad
for your brain, like many things.
Sometimes good and sometimes bad.
Why is that?
Because you get cerebral vasoconstriction, a leftward shift of the hemoglobin global
oxygen dissociation curve means you get less flow, and the blood that does flow to the
brain is less able to give it oxygen.
Plus, with hypercapnia, you get an increase in seizure potential, increase in metabolism.
So it does exactly the wrong thing for O2 supply-demand.
And if you have a patient, for example, with hyperventilation and severe DKA and you intubate
that patient and normalize your CO2, you'll cause great harm.
You can see here, a small-- seems like a small-- increase in CO2 gives a big decrease here
in CSF pH.
And when the patient, in fact, is particularly hyperventilating to begin with, that increase
is a whole lot greater.
And many of us have seen first or secondhand a kid with metabolic encephalopathy hyperventilating,
low CO2, gets intubated, CO2 normalized, and that patient can herniate and die.
You can see here a patient with Moyamoya syndrome with cerebral CO2 given.
And there is lighting up only of the left side of the brain.
And with corrective surgery, you can test the cerebral circulation and see that the
brain is not perfused.
So like everything else, is there a balance?
It's not as if too much too little will be good for every patient because patients are
different in groups and patients' organs are different and their diseases are different
at different times of their illness.
So we do not know how to balance CO2 except maybe to prevent cerebral herniation or cerebral
pulmonary vasoconstriction.
So there is undoubtedly a balance.
There's evidence of benefit and evidence of harm in almost all areas of this.
Here's a good example to finish up with.
Doctors Tasker and Peters provided this image here.
This is a young boy with ARDS.
And here, you would naturally go for a lung protective ventilation however you do that.
When you do that, you're going to get hypercapnia which would be fine except this poor boy has
ARDS from meningoencephalitis and systemic meningococcemia.
And so hypercapnia here might be fine with low stretch.
Won't be fine at all here, at least not acutely.
So with the CVO2 mounter, they were able to actually titrate this to get a decent outcome.
In summary, hypercapnia works in some experiments, but not all of them.
It seems safe clinically.
At the bed side, you have to judge things as best you can.
And it's a mixed picture.
People think we need outcome studies.
I suggest that we wouldn't even know how to design an outcome study for hypercapnia at
this stage.
Thank you very much.