These are my conflicts of interest, which are not really relevant for the present talk.
And so I think we have to start with one question, which is what are we really measuring with
Positron Emission Tomography?
As the title of my talk somehow suggests that PET is measuring inflammation, which is exactly
not the case.
You are measuring something that approximates inflammation.
So just a few words on the very basic principles of PET, which most of you are probably familiar
with.
We are basically injecting in the patients deoxyglucose, labeled with a radioactive isotope.
And so this enters the cell and is then trapped after phosphorylation into the cells.
It is the oxyglucose, so it cannot go any more towards the Krebs cycles.
And so really, what we are imaging that with the emission of a positron from this molecule
is the rate of metabolic activity of the cells, how much glucose the cells are picking up,
how much the cells are metabolically active.
And of course, for this reason, PET is widely used for the study of cancer, which heavily
depends on anaerobic glucose metabolism.
But inflammatory cells, and particularly neutrophils, are also avid uptakers of FDG.
And in this study that we've done with the-- I'm sorry, the reference is down here-- with
Dr. Musch, published in Anesthesiology at the time of my fellowship in Boston, we did
a unilateral model of ventilator induced lung injury.
And you can see, it was a very tough model for the animals, carried on in the right lung.
And you can see how the right lung is picking up glucose, is showing up brightly.
Why is that?
Because it is full with neutrophils, and all the neutrophils are picking up FDG.
And if we can induce a neutrophil depletion, what we see is that the FDG signal is going
almost to zero, corresponding to a decrease of the circulating blood cells.
This is another study from our own group, Dr. Zambelli.
And we've use induced a unilateral lung injury by acid installation in mice.
So this is micro PET.
Here, you see the injury on the micro CT, and you see the FDG signal in the injured
lung.
Now, it's interesting to see how the uptake of FDG is correlated with the number of neutrophils
and macrophages present in the ex vivo microscopy of these animals.
And in fact, in recent years, more and more data are showing that not only neutrophils
could be responsible for FDG uptake, but-- these are data again from the Boston group--
but that depending on the type of injury that the lung underwent, there can be a significant
uptake also from endothelial type II cells, macrophages, and neutrophils.
But still, neutrophils are responsible for the largest amount of the signal that we see.
And so these were the premises for our study, the rationale for our study.
The fact that FDG-PET can be used to assess metabolic activity in the cells, and that
in the setting of lung inflammation, this metabolic activity can usually be ascribed
to inflammatory cells.
And we know that there is a major role of neutrophils in the onset, in the generation
of ARDS, and in the perpetuation of the disease, and of ventilator induced lung injury.
So on we went with this study, which began with some I would say simple goals, which
were to establish the metabolic activity of the lungs, or if you will, the inflammation
of the lungs in patients with ARDS, and to describe the distribution in the space in
correlation with the corresponding CT scans.
This is the study population that we enrolled, 17 patients overall.
And you will see that we actually did two studies, so not all patients are included
in both.
17 patients with what we would now call just ARDS.
At the time, there was still ALI RDS.
They were not exactly in the early phase of the disease.
So the mean was nine days of intubation, but the standard deviation was very large.
Quite hypoxic, and the PEEP was I would say in a rather high ballpark figure, because
it was 12 with considered a safe plateau pressure on average, and protective tidal ventilation.
This is the imaging protocol we use.
And once again, I have to thank all my colleagues, who really were supportive through this tough
study.
We brought the patients who had an indication, already a clinical indication for a CT, and
this was required by our IRB, not just to have a CT scan, but in adjunct they would
also have a dynamic PET.
So we did the CT scan, injected a bolus of radioactive glucose, and did an image of PET.
And from this image with some mathematical models I will not get into, we derived this
parameter, KI, which is basically a number that tells you how much glucose is being picked
up at the whole lung level at a given region of interest that you want to look at.
So KI is really the rate of FDG uptake, which once again, if you will, can be used as a
proxy for inflammation.
These were the results of our first study, published online, Critical Care Medicine.
And we did show that all patients with ARDS had a diffuse inflammatory activity.
And this is the KI of the normally aerated tissue of our subjects.
And you see how on average this is much, much higher than the controls, with an about seven-fold
increase, as compared to controls.
And this was in the tissue that on CT scan looked as normally aerated.
So on the so-called baby lung, it did look normal on CT scan, but it was not normal at
all.
It had seven times the metabolic activity of the healthy controls.
And another thing that we've seen is that while in some patients we got this kind of
pattern that we would expect, that I would have expected before beginning the study,
so that the areas in which most of the collapse was going on had the greater inflammations,
in other patients, the pattern was reversed.
It was the other way around.
And we had areas which were somehow aerated, but that would pick up more FDG than these
regions, dorsal collapsed, that had no ventilation at all.
So this was kind of an observational study.
And our findings were somehow confirmed recently by this paper, published in Critical Care
Medicine by João B Borges, working in Uppsala with Professor Goran Hedenstierna, who has
shown that in a model of VILI, of Ventilator-Induced Lung Injury, the greatest difference between
controls and injured animals occurs in the normally aerated and poorly aerated lung.
So this somehow confirms that the normally aerated tissue once again looks normal on
CT scan, based on density criteria, but there is inflammation going on there.
There is a battle going on there that we don't see just looking at densities.
So the second part of our study was to assess what could be the relationship between the
regional deformation induced by tidal ventilation and metabolic activity, or once again, inflammation,
if you will.
And I know this is a little bit schematic, but for the purpose of our study, we divided
the potential mechanism of-- we identified the two main mechanisms of ventilator induced
lung injury, one being cyclic opening and closing of alveoli, or so-called atelectrauma,
and the other one being overdistension or distension of a lung which is already ventilated.
And once again, I know this is a bit schematic, but I think for our framework, it was quite
a useful distinction.
So the results of this study were published in this paper, 2011, in the Blue Journal,
where we had to put in a title not inflammation, but regional metabolic activity, as the reviewers
would not allow us to write inflammation.
But I think the paper would have looked much more fancy if we could have written inflammation.
But anyway, that's how the things went, and you live, you learn.
So we added two CT scans at the end of the study, one done at PEEP, and one done at plateau
pressure.
That would allow us to establish the deformation of the lung induced by tidal ventilation.
And so if we look at the first mechanism to identify the regions of the lung that were
being cyclic opened and closed, we identified some regions of interest, the first one being
this blue lung, which is collapsed both at end-expiration and end-inspiration.
And here we could compute the inflammation of this region, which is always collapsed.
And here in red is the lung that is collapsed at end-expiration, but then gets aerated at
the end of inspiration.
And this was-- there was a first automated segmentation, but then we manually reviewed
each CT slice to avoid that this was somehow due to a movement of the structure, that it
was a real opening and closing.
And so also for these regions, we would compute the KI of the regions undergoing cyclic opening
and closing.
And with our-- I would say-- big surprise, we found no difference.
So the KI of the regions that are recruited throughout the respiratory cycle is not different
from that of the regions who undergo cyclic opening and closing.
And this does not mean at all that atelectrauma is not injuring the alveoli.
There's a ton of evidence that shows that if you open and close, cyclically, an alveolus,
this would induce injury.
What we found, however, was that in our clinical setting with the ventilatory strategy that
we did apply, the amount of this tissue was just a little bit of the total weight of the
lung.
It was no more than 3%.
So what these data show is that probably in our setting, we haven't seen a signal because
the amount of lung being open and closed was relatively small.
The second mechanism we focused on was the distension of the lung which was already ventilated.
And we focused mostly on the normally aerated lung, and we found a statistically significant
correlation.
I mean, it's not a huge number of patients, but this is a kind of a physiological study.
We found a statistically significant correlation between the inflammation of the normally aerated
tissue and plateau pressure.
And there was a steep increase of the inflammation above 26, 27 centimeters of water.
And now of course, this is a bit of the egg and the chicken question, because we couldn't
think if this is just an association, that the worst patients have a higher inflammation
and higher plateau pressure, or if there is any kind of cause-effect relationship, so
that the higher plateau pressure is somehow causing a higher inflammation of the normally
aerated tissue.
And we cannot give a definitive answer to this question, of course.
The only way we could think of approaching this issue was we've measured the KI, the
inflammation of the tissue which is not aerated, which is not exposed to tidal ventilation.
And this, if you would allow me, is a kind of a baseline inflammation for the lung.
And then we took the KI of the normally aerated tissue, which is exposed to ventilation.
And so the ratio between these two might allow us to dissect a little bit more the effect
of ventilation.
Because this KI would see both the ARDS process and the ventilation, while this KI is more
likely to see only the ARDS process.
And to make a long story short, we found that the correlation was still there, and it was
even more significant.
So plateau pressure is associated to a higher inflammation of the normally aerated tissue
potentially having a causative role in this.
But once again, I would be very cautious stating that.
When we looked at tidal volume, we've seen no association between tidal volume in terms
of predicted body weight and KI.
And once again, this does not mean at all that tidal volume, high tidal volume is not
causing lung injury.
We know that very well.
The problem-- I mean, not the problem-- the situation here is that these patients were
being treated.
And so what happened is that likely severe patients got a reduction in tidal volume,
and so we would not state that tidal volume is not causing lung injury.
But there are more and more data coming out of the literature, more or less in the same
time.
Our colleagues in Milan, Alessandro Protti, were doing these studies, where they show
that what they call strain, which is the ratio of tidal volume over FRC, is a major determinant
of lung injury-- of ventilator induced lung injury.
So they randomized piglets to different tidal volumes, and they measured this ratio.
So what is the ratio of tidal volume to the space that the tidal volume can occupy in
the lung?
And as soon as this strain went up, there was a huge formation of edema and a change
in lung weight.
And so more or less at the same time, we did the same thing.
And we measured the tidal of volume that is distending the normally aerated tissue, in
comparison with its relaxation volume.
So we have a given end-expiratory lung volume, and this gets an inflation.
So this ratio is somehow similar to the strain.
It's not exactly the same, but is quite similar.
And in this case, we found that this instead was really associated with KI itself, or KI
normalized by the KI of the ventilated tissue, normalized by the KI of the not ventilated
tissue.
So suggesting that the ratio of tidal volume to end expiratory lung volume, which once
again is not exactly the strain but is close to what is being called strain, is highly
associated with lung inflammation.
And lately-- one year later, this paper by the group of Albaiceta came out.
And they've shown basically the same thing with a very different approach, which is that
if the strain is slightly high-- is above strain defined the way we did, so tidal volume
over end expiratory lung volume-- is above 0.27 and the numbers are in the same ballpark
like the ones we found, there was a much higher circulating inflammatory activities than if
the strain was lower than 0.27.
So getting to my conclusion, I think that PET data give a direct evidence of the fact
that in humans, in human patients with ARDS, the baby lung is in fact inflamed.
We haven't been able to see any evidence in our patients of injury caused by atelectrauma,
but once again, this does not mean that atelectrauma would not cause acute lung injury.
That the inflammation of the tissue which is being ventilated is associated both to
a higher-- to a plateau pressure, particularly if above 27 centimeters of water, and with
a ratio of tidal volume to end-expiratory lung volume.
And with this, I thank you very much for your attention.