Good afternoon.
My topic is an area that I've been interested in now for 15 years, which is the potential
clinical and physiologic significance of elevated pulmonary dead space in patients with ARDS.
I'm going to go back and give you the history of how we became interested in this.
First are my disclosures, and so then I'll go on from there.
So pulmonary dead space in ARDS-- five themes.
First, background and rationale.
Second, primary results from our initial study, plus follow-up studies from us and other investigators.
Mechanisms that might explain the elevated dead space in patients with ARDS.
And then the question of whether or not we can or should estimate pulmonary dead space
versus measure it.
And then the conclusions.
So everyone knows that the classic physiologic abnormality in ARDS is hypoxemia.
The patient's chest x-ray, as shown here, has bilateral airspace opacities.
And the histologic picture shows alveolar filling.
And the hypoxemia's secondary to alveolar filling, and also some degree of atelectasis
of the alveoli, resulting in low V/Q and frank interpulmonary shunting.
But we've noticed in ARDS network, and other clinical trials, for many years that the baseline
minute ventilation in patients enrolled in clinical trials is virtually always elevated
to about twice normal.
So if normal minute ventilation's about 6 liters, it's consistently 12 liters.
And this is in early ARDS.
And the question is, why?
We reasoned that either there is a marked increase in carbon dioxide production or an
increase in alveolar dead space.
Now, many years ago, Julius Comroe from the University of Pennsylvania, who founded our
Cardiovascular Research Institute at UCSF, published this simple diagram to illustrate
how dead space really occurred simplistically in the lung.
And you can see here, on the side where the B is, that we're talking about is ventilation
to an alveolar unit that does not have blood flow.
Now, there could be variations on a theme here.
There could be reduced blood flow as opposed to no blood flow.
But that's the basic idea.
And I always say, on rounds in ICU, what this means is high V/Q. People are so used to saying
V/Q mismatch.
I think that's an inadequate statement.
I think patients should be described as having a high V/Q, such as this, which will cause
dead space, or low V/Q, which is more associated with hypoxemia.
So the hypotheses for our initial study are shown here.
The dead space fraction is elevated early in ARDS.
And, two, an elevated dead space fraction will have an independent predictive value
for identifying ARDS patients with a high mortality.
So to test this hypothesis, we did a study over three years at both our University Medical
Center and our city/county hospital in San Francisco.
179 patients were prospectively enrolled, and we collected clinical pulmonary and severity-of-illness
data.
At that time, we measured the dead space with a bedside metabolic monitor, the DELTRAC--
normally used to help guide nutritional replacement.
We of course calculated the dead space fraction with a modified Bohr equation, where in the
numerator, you have arterial PCO2 concentration divided by mixed expired CO2-- not to be confused
with end tidal CO2, but mixed expired CO2-- divided by the arterial PCO2.
So in us, right now, my PCO2 is, let's say, 40.
My mixed expired CO2 is 30.
If you put 40 in the denominator, it's 10 divided by 40, or 25%, as a proximate normal
dead space, reflecting largely anatomic dead space.
Tidal volume in this trial was a mean of 10 +/- 1.4 mL per kilogram.
We were just at the cusp, the turnover period, to low tidal volume, an issue I'll come back
to.
And we also measured static respiratory compliance.
Patients were a mean of 48 years old, a little younger because of the inclusion of patients
from the city hospital.
Clinical disorders-- sepsis, 25%; pneumonia, 31%; aspiration, 11%; major trauma, overdose,
and so on, 34%.
Overall mortality, 42%.
Now here are the baseline characteristics.
P/F was 147, pretty severe.
Tidal volume, as I mentioned, 10 mL per kilogram, ideal body weight.
Respiratory compliance.
Minute ventilation, just as we anticipated, was twice normal, 12.1 liters.
Dead space fraction overall was 0.58, so quite elevated if a normal, as I'll show you, is
around 0.35 to 0.38 in a normal ventilated patient without lung disease.
Statistical analysis was done as the primary outcome variable of death before hospital
discharge; logistic regression; SAPS II for severity of illness; and multiple logistic
progression for independent association with death.
Now, at the end of the study, there were several univariate variables that were associated
with death, which you would expect.
And let's just go through them briefly.
The P/F ratio was lower in non-survivors.
The dead space was 0.63 in non-survivors and 0.54 in survivors.
Respiratory compliance was lower in those who died.
Lung injury score was higher in those who died.
SAPS II was higher.
And as you would expect, sepsis was higher, 51% versus 31% in those who died.
Vasopressor use was about twice higher.
The low tidal volume protocol was just making its way into clinical practice.
Just a small number of patients-- 31-- but of course, it makes sense that it was more
common in the survivors.
Cirrhosis-- not quite significant.
And NPOFC is Non-Pulmonary Organ Failure.
So then we put this into a multivariate analysis, and the three variables that turned out to
be independently predictive of mortality are here.
Pulmonary dead space fraction, with the highest odds ratio-- it had a 0.002 value; SAPS II,
index of severity of illness; and respiratory compliance.
All the others fell out.
And looking at the data just in a figure, you can see here the early elevation of dead
space.
And these were done within 24 hours of the diagnosis of ARDS.
And you can see that the median was 0.58 in ARDS versus ventilated controls, where it
was 0.36.
And here's the data for non-survivors versus survivors.
It was significantly higher in the non-survivors versus survivors, as I've already said.
And you can see there's a pretty good separation there.
And then when we broke the data down according to dead space fractions, taking increments
as shown in this figure, with mortality on the y-axis and dead space fractions on the
x-axis, you can see, at the cutoff, around 0.57 to 0.61, the relationship to mortality
began to increase sharply in those two bar graphs.
And then in a follow-up study published two years later by Rich Kallet one of the key
authors of this work, we found that measuring dead space at later time points in ventilated
patients with ARDS still had predictive value for death.
Perhaps not a surprise, but it's shown here for day 1, day 2, day 3, and day 4.
I think the most important observation was day 1, but still, this shows there was a continuing
association with a poor outcome.
And then, in part because we wanted to see if this still was true in the low tidal volume
era, we did a follow-up study in 42 patients with ARDS, this time measured by volume capnography,
the simple bedside method that I'll come back to.
All patients were ventilated with 6mL per kilogram ideal body weight tidal volume.
And the baseline pulmonary dead space again was predictive of death-- 0.61 versus 0.53.
And several other studies have continued to confirm this.
Work from Dr. Pesanti's and Dr. Gattinoni's group, published in the New England Journal
in 2006, found that elevated dead space has predictive value for mortality in ARDS.
A study we did at UCSF, with Kathleen Liu leading, showed that elevated dead space,
when combined with a biologic marker, Ang-2, was predictive mortality.
And then there was this study in Chest in 2010 that also confirmed this.
What accounts for this increase in dead space fraction in early ARDS?
Well, we don't know precisely.
But the two possibilities, it seems to me, are thrombotic or inflammatory injury in the
pulmonary capillaries, the microcirculation, and/or obstruction of blood flow in the extra-alveolar
lung circulation, resulting in areas of high ratio of ventilation to perfusion.
And many years ago, over 30 years ago, at Mass General, there was a group led by Warren
Zapol that was studying the pulmonary macrocirculation.
And they did angiograms in patients in whom they had pulmonary arterial catheters, and
they wedged the catheter and injected dye.
And they identified, in fact, macrovascular obstruction in many of these patients.
In fact, they found it in about half of their patients, and it was associated with severe
ARDS, presence of DIC, pulmonary hypertension, and a poor outcome.
Again, this is in the era before lung-protective ventilation.
And they also did very well-done studies of patients who died and found obliteration of
a lot of the lung capillaries in patients who succumbed later, with thrombosis, medial
thickening, and decreased vascular density.
Now, the issue has come up-- could we just estimate dead space fraction, rather than
measure it?
And to answer this question, Jeremy Beitler, of highly-motivated, bright pulmonary critical
care fellow at Beth Israel in Boston, under the supervision of Danny Talmor, worked with
several of us, including Taylor Thompson, to evaluate four different methods for estimating
pulmonary dead space.
The different methods are listed here, and they were done in patients in whom we had
data for, actual measurement of dead space fraction.
And I'll just show you the results here.
The manuscript is not yet published.
I think it will be soon.
But the main point to appreciate here is of the four methods tested, only the Harris-Benedict
one in the upper right-hand corner or left-hand corner, actually had some reasonable relationship
to the measurement of dead space.
Harris and Benedict predicted measured VD/VT to within +/- 0.10 in 70% of the patients.
But that's not really terrific, when you think about dead space.
If the dead space were 0.65, it could be wrong in the direction of 0.55 or 0.75.
So it's not great.
And if you took all 95% of the patients, the standard deviation was 0.20, which is quite
a lot.
It also was less accurate when the PCO2 was less than 30.
So if you had to estimate, this would be the one to use.
But it's not terrific.
Further data in this slide just shows that compared to all the others, the Harris-Benedict
was the best for mirroring the actual measured VD/VT association.
It was within 7% of measured VD/VT in all quintiles.
It did improve predictive validity for mortality when we added it to the Berlin definition.
The Berlin definition didn't have patients in whom dead space was measured, and so they
were hampered by that.
There's nothing they could do about it.
But if we added this to the Berlin Definition using this estimate, it did improve the mortality
prediction.
So it has some value, but our conclusions are VD/VT should be measured in future randomized
clinical trials to facilitate secondary analyses to shape research and practice.
The Harris-Benedict estimate best predicts the measured VD/VT and association with mortality
on a group level.
It did enhance the predictive validity for death over the Berlin definition alone, but
I don't think it's adequate for individual care and has the limitations I said.
And just to close here, I would just would like to make a plug for volume capnography.
It's very straightforward to measure.
Right at the end of the endotracheal tube, you get the mixed expired CO2, you get a blood
gas, and you can measure the VD/VT straight away.
And this is data from Rich Kallet that shows that with using one of the commercial methods--
not that I'm plugging it, though-- to measure mixed expired CO2 with a NICO monitor.
So in conclusion, elevated dead space fraction predicts mortality and ARDS, a finding that
has pathogenetic significance.
Thrombotic and inflammatory injury to the lung microcirculation is probably a major
early mechanism of lung injury in ARDS.
And I believe that measurement of pulmonary dead space should be done in clinical research
and trials in ARDS whenever possible.
Thank you.