>> So, first of all I would like to thank the society
for [inaudible] me to give this presentation today.
It's a real privilege to present the PReVENT Trial results that are going
to be published just right now at JAMA.
Not only do I want to thank the European Society of Intensive Care Medicine but also the sponsor
of the study, which is a Dutch organization ZonMw, abbreviated, and without their help,
this study would not have been possible.
As I mentioned already, this study is going to be published just now, I think,
and I would like to thank the editorial board, especially Derek Angus for his kind help,
and without his support, this would not have been possible
to publish it this fast and in this way, I think.
And finally, I would like to thank everyone who was involved in the trial,
especially the coordinator of the trial, Fabiana Simonas [phonetic], also present today.
Without her help, we would not have been able to recruit so many patients and come
to the results as I'm going to discuss today.
So let me first try to give you a little background for why we did the PReVENT Trial.
We all know for many years that it makes sense to reduce tidal volume size
in patients with ARDS based on this study.
Although we must say that this study was using a very low tidal volume
or at least a low tidal volume of 6 versus 12, which is now seen as quite high tidal volume,
and it was not testing something in between.
Now the majority of patients in the ICU are not having ARDS, and these patients may also benefit
from a lower tidal volume strategy, and this was suggested by a metaanalysis.
This is an IPD metaanalysis from our group showing that there is indeed a difference
in outcomes like ventilator-free days when you compare groups in a low tidal volume group
versus a high or higher tidal volume group and also published at another place,
but from the same IPD metaanalysis we found differences in other end-points.
Now I would like to stress if you look at IPD metaanalysis,
especially when it's taking studies, or randomized clinical trials, over a longer period
of time that there could have been many things changed in time.
And if, for instance, larger tidal volumes were used in the previous or the first trials,
it could very well be that what we found here is simply a reflection of an improvement in care
and not so much a change in the tidal volume size.
And besides that, we are not sure if we can use low tidal volumes without paying a price.
For instance, some of us would say you need more sedation in these patients
because of more patients with ventilator asynchrony or you get a higher respiratory rate,
which is not going to be accepted by the patient or maybe
by the nurses and doctors at the beside.
There could be something that we call self-inflicted lung injury as a compensation
for the low tidal volumes that we want to give to patients.
The patient just wants to breathe more and by that is creating higher pressures.
And finally, some of us say there's a risk of delirium when you use low tidal volumes
because of all these previous things.
Now how are we world-wide setting tidal volumes
and other ventilator settings in patients without ARDS?
We tried to give an answer to that with the PRoVENT study,
which actually preceded the PReVENT study.
This was an observational study in approximately 1000 patients in 16 countries, 119 ICUs,
and you clearly show on top that there is a sort of distribution,
which is maybe a biological distribution, some would say,
but the median tidal volume is approximately 8, so this is what we are doing.
But you also notice that quite some patients, 40 percent, are receiving higher tidal volumes
and 60 percent lower tidal volumes.
So, we wanted to test the hypothesis
that a ventilation strategy using low tidal volumes is superior
to a ventilation study using intermediate tidal volumes with respect to the number
of ventilator-free days at day 28.
We did a randomized clinical trial in the Netherlands, six centers in full.
We had a pre-published protocol and statistical analysis plan was finalized before closing
the database.
We had the study approved, of course, and we used deferred informed consent,
I will explain later on, and we had the DSMB overlooking the study and conduct of the study.
We included patients that were intubated shortly before, within hours, for instance,
in the OR or in the emergency department or in the ICU not having ARDS,
expected to be on the ventilator for at least 24 hours.
And we wanted the patients to be randomized within the hour.
That was the reason we deferred informed consent because it's impossible
to have the family take a decision on whether or not to participate of their beloved people
and then have a study that's only randomizing after 24 hours with regard
to mechanical ventilator settings.
And as I said, these were patients without ARDS, but also COPD was an exclusion criteria,
and I would like to refer to the JAMA paper
where we mentioned the additional exclusion criteria.
There was a 1:1 randomization done by a local investigator using a dedicated website.
We used block sizes of two to six patients randomly, and we had stratification for center
and for intubation location, that is, in the ICU or just before arriving into the ICU.
These were the two interventions tested.
So we had a low tidal volume versus an intermediate tidal volume strategy.
All patients were on volume controlled ventilation or pressure support as soon
as possible, and the tidal volumes targeted were 4 to 6 mL per kilogram predicted body weight
in the low group versus 8 to10 mL per kilogram in the high or intermediate tidal volume group.
This does not say that the patient could not receive higher tidal volume
in the low tidal volume group.
For instance, if there was a high respiratory rate noted, then the nurse
or the doctor could increase the tidal volume [inaudible].
This was the target.
And the same for the intermediate tidal volume group
when the plateau pressures were rising too much, may be an indication by the way of ARDS,
then it was allowed to lower the tidal volume.
Oxygen targets are as here in the table, which are conservative, and we had PEEP FiO2 table
for titration of the PEEP and the FiO2,
according what has been published by the ARDS network.
And finally, importantly, in our centers, every eight hour there was a look
by the nurse and/or doctors whether the patients were ready for weaning,
meaning they had to switch for pressure support to see if that was possible and also
for extubation readiness transaction at least eight hours, but more was possible.
We used analgosedation and muscle relaxation, but this was not used
to allow the higher or lower tidal volumes.
It was just used as standard of care where deemed necessary.
We asked them not to have a tracheostomy before day 10,
and we had some additional standard of care remarks in the paper.
For sake of time, I would like to refer to that one.
But the primary endpoint that we used, as I already mentioned,
is the number of ventilator-free days and alive at day 28,
and we use this because we think it's an objective patient center and also relevant
and maybe even cost effectiveness relevant endpoints.
We also looked at ICU and hospital lengths of stay, and we looked at 28-and 90-day mortality.
We focused, also, on the occurrence of pulmonary events, such as the development of ARDS
or pneumonia or pneumothorax, and we looked for sedative use and the occurrence
of delirium and also blood transfusion.
The statistical analysis plan was based on a power calculation to have
at least 467 patients per group to show a difference of one day
of ventilator-free days at day 28.
From an intention to treat analysis, we used Kaplan-Meier curves to show differences
if they were between the groups over time, and we did some subgroup analysis,
the most important one being whether the patient was having pneumonia or not having pneumonia.
The results are as follows.
We had a randomization, which led to two comparable groups of patients,
and I would like to refer to table 1 in the JAMA paper.
I would also like to stress that we had to exclude quite some patients, 60 percent,
and the majority of, the most important reason was that a one-hour delay,
or a one-hour timeframe was very short.
It was very difficult to do the randomization in time.
Still, you could say, we were able to recruit so many patients.
And 80 percent of the patients, by the way, were medical.
So what happened with the tidal volumes, you can see it here.
On the top, I showed for volume-controlled ventilation, on the bottom I showed
for pressure-support ventilation.
You see that there is a discrimination between the groups, which [inaudible] for day one,
day two, and day three, more with volume-controlled ventilation
for reasons you will understand and would like to show the other data not on slides,
but you can read it in the additional E tables.
Not surprisingly, the difference in tidal volumes also resulted in difference
in respiratory rate, as shown in this distribution plots.
Here, you can see that a low tidal volume was associated with a higher respiratory rate
and vice versa, and intermediate tidal volume strategy was a lower respiratory rate,
and this sustained over the first four days and also thereafter, by the way.
The primary endpoint of the study was ventilator-free days, and as you can see here,
there is no difference with regard to this endpoint.
The number of ventilator-free days was 21 in both groups.
And also when we look at the other endpoints, as shown on one of my previous slides,
you see here the Kaplan-Meier curves nicely showing there is no difference
between the groups, between the randomization groups.
And when we looked at the subgroup analysis, pneumonia versus no pneumonia,
also there we found no difference.
So in conclusion, a strategy, a ventilation strategy
with low tidal volumes is not more effective than a strategy
with an intermediate tidal volume with respect to the number of ventilator-free days.
I think this study is having several strengths,
having a clinical-relevant patient-centered endpoint.
We had several measures against bias, and we had a short window for inclusion prevention dilution
in the first hours of mechanical ventilation in both arms.
Also, there were weaknesses, of course, what you can expect with a ventilation trial.
It was not blinded.
It was something we had to accept, and it was a heterogenous group
of patients, but it was also expected.
Finally, quite some patients were missing because of reasons I explained.
Still, I would like to applaud the researchers who were able to recruit
so many patients in such a short time.
Now, a little bit more interpretation.
If you look at the hypercapnia, I realize I did not show you this
in the slides I showed here before.
We saw that a low tidal volume strategy was associated with a slight hypercapnia
in some patients, also something maybe you can expect.
And we all know that hypercapnia may have deleterious but also beneficial effects,
and we are not sure if this was causing trouble with the interpretation of the data.
And also of interest was that there was less efficient alveolar ventilation
with the low tidal volume.
So, actually it was more [inaudible] ventilation, especially when the patients were
on volume-controlled ventilation, not so much with pressure-support ventilation.
And finally, how to interpret the data.
With all the evidence or circumstantial evidence we had from the last studies,
maybe we should conclude that the distending pressures that were used in patients
with intermediate tidal volume strategy were already so low
that maybe it would not expect harm from those tidal volumes.
Maybe that was already protective enough.
I would like to draw for one minute attention to this study.
This is a mechanical power.
I think you all know the discussion which is going on, mechanical power,
the [inaudible] being transferred from the ventilator to the patient with every breath,
possibly causing harm, and there are several factors that can be unified
into this mechanical power [inaudible], probably all having a role in development
of ventilator-induced lung injury, and one of them is tidal volume,
but the other one is respiratory rates.
And seeing the fact that we had a higher respiratory rate,
it could well be that the lower tidal volume was actually not only giving benefit but also harm.
So coming to one of the questions, maybe [inaudible] is going to ask me it,
how would I design the next trial.
I would probably not only focus on tidal volume but maybe also
on mechanical power if this is at all possible.
Here is where I would like to thank you for the attention and give back [inaudible]
to the chairs and happy to take any questions.
Thank you.
[ Applause ]
>> Paper is open for questions/discussion.
>> May I?
>> Massimo.
>> Did I understand correctly there were proportional patient were
on spontaneous breathing with pressure support?
Okay. If it is so, how was the proportion, and, by chance, have you done a stratification
of your sample to see if there were differences between those who were on spontaneous breathing
and those who were fully mechanically ventilated?
>> That's a very good question.
First of all, we allowed pressure support, of course, and this is an important difference
with previous studies in which patients were on volume-controlled
or pressure-controlled ventilation with a mandatory mode for a much longer time
as compared to what we do nowadays.
And second, we did not officially do this, but we looked into the database
and did not find a difference, neither with respect to the proportion in time,
neither with respect to the primary endpoints.
>> Thank you.
>> Marcus, Gordon Rubenfeld and Manu Shankar-Hari have an accompanying editorial,
and one of the issues that they point out is that the difference
between the two groups wasn't as substantial as you had hoped it was.
In part, this has to do with the algorithm you developed allowing some individual physician
decision making.
Do you think that creates a slightly different interpretation of the results?
>> Yes, in part.
I had just five minutes to read the editorial, so thank you for summarizing it so nicely.
Indeed, it could explain in part some of the results.
But on the other hand, this was a very pragmatic study, and the nurses were quite well trained
in how they should apply the low or the intermediate tidal volume.
So, another way to look at the data may be, and I think this is also what Gordon Rubenfeld wrote
in his editorial, will this study now change our practice.
If you look in the PRoVENT study, the tidal volume was 7.8 medium.
Actually, if you look at the two arms in the trial, they were plus
or minus one milliliter surrounding that, so maybe it will not change what we are doing
at all, and maybe we should make the groups even different much more,
but [inaudible] in the low tidal volume group that for instance we cannot use pressure support
or we should sedate these patients more,
and we explicitly did not want that to happen in our patients.
And also in the other arm, the intermediate tidal volumes,
the only reason to reduce the tidal volume rise was a rise of the plateau pressure above 25,
which I think is what we still at this moment think as a safe zone.
So we didn't want to cause harm.
>> Probably [inaudible] pressure was within a safety limit as well
as the transpulmonary pressure, but I think that you didn't view, you didn't measure it.
>> We did not measure it.
It was not possible to do this in this trial, but there were some patients
in which we could measure this, and there was the driving pressure measured
in several ways was always in the safety zones.
>> Thank you, Marcus.
>> You're welcome.
>> Thank you very much.
[ Applause ]