>> Howard Bauchner: Hello and welcome to conversations
with Dr. Bauchner, it's Howard Bauchner, Editor
and Chief of JAMA. And today I'm joined by
two of my favorite people, Derek Angus. Derek
is an Associate Editor at JAMA. He's also
the distinguished professor in Mitchel P.
Fink Endowed Chair, Critical Care Medicine
University of Pittsburgh Medical Center, where
he's Director of the Department of Critical
Care Medicine. And Maurizio Cecconi, who joins
me having followed our March 13 livestream
event. Maurizio is the Head of the Department
of Anesthesia and Intensive Care Units at
the Humanitas Research Hospital. Humanitas
University's President Elect of the European
Society of Critical Care Medicine. I would
say both of these individuals are stars in
critical care. I would call them legends but
they're both too young to be legends. But
they are on their way to legendary status.
For the listeners today this is going to be
about critical care medicine. So, I'm delighted
to entertain questions from the listeners
but, hopefully, they will be relevant to critical
care medicine. We're going to discuss five
or six issues. First, the general epidemiology.
Respiratory support, phenotypes therapy, and
at the moment, a generally neglected topic,
what do we know is evolving around post-acute
care of individuals who've been in the ICU?
So, Maurizio, starting with you. Anything
new about epidemiology or are the data pretty
well established? Who the risk -- what's the
major risk characteristics, risk factors?
What's the mortality look like in the intensive
care unit?
>> Maurizio Cecconi: So, hi. Howard, [inaudible]
everyone. I guess, for me, the last few weeks
seeing around how it has been evolving around
the world, has confirmed a little bit what
we've seen in Italy in the first few weeks.
If you remember when we talked the first time,
we were looking, for instance also, how case
fatality rate was quite high in Italy compared
to some other countries. And one important
issue, I think, is that because we have a
disease for which we don't have a vaccine
and we don't have specific therapies, yet.
It seems to me that probably one of the biggest
differences that we're seeing around the world
is how well systems are able to protect more
vulnerable people. And for instance, in Italy,
our median age is 62 years of age, which stays
pretty much the same probably throughout the
pandemic. But if you look at the case fatality
rate for the decades of age when you start
to go above 60, 70, and so on. They are quite
high. And for instance, if you're looking
at in Europe, other countries despite having
a lot of infection, they seem to have done
better. I would say, I would call Germany,
for instance, they seem to have done a pretty
job probably in contact tracing and looking
at cases and so on. But, again, if you look
at the median age, the median age of their
population is quite lower compared to Italy.
It's about, I think, 49, 50 years of age.
And so one of the things that I would say
is really, if you're able to protect from
getting the disease the older population seems
to be a pretty good thing to do if you can
achieve that. In Italy, in the U.K. I worked
in the U.K before, so I stayed in touch with
colleagues and I know a little bit so while
the disease spread there, for instance, with
significant problems, with long-term facilities
and nursing homes. So, you know, if the disease
spreads in those facilities where you have
vulnerable old people, I think it's really
bad and a lot of those populations, actually,
they have a very high case fatality rate.
For all concern intensive care, we do know
that if you are, again, old and, male, and
with hypertension, it seems to be a common
trait of people that come to intensive care.
But, again, we're seeing a high variety of
age groups coming to intensive care. Pediatric
population, they are very rare to see becoming
sick. That's a good thing. But what concerns
the other group, again, are the median age
was 63 and longer, which takes into account
about 75% of the old patient population that
had coronavirus in Italy.
>> Howard Bauchner: Derek, in Pittsburgh,
for the people who make it into your ICUs,
and I know you have many, what's your sense
of what the mortality rate is?
>> Derek C. Angus: It really depends on the
age distribution. So, in Pittsburgh, now,
most of our ICU admissions are actually coming
from nursing homes. And I would say in general,
that the nursing home mortality rate among
patients who are infected is in that 20- to
30%. And those who get admitted to the ICU
and get intubated, it's even higher, obviously.
The patients who get sick but were reasonably
healthy beforehand, they just had a comorbidity
but they weren't 80 years of age, I would
say, I mean, it's ever evolving. But we definitely
get a lot of patients who end up becoming
long-stay on the ventilator. Other than the
subset who become long-stay on the ventilator,
the mortality rate, I would say, would be
at the low end of ARDS. There's quite a lot
of people who get intubated and do well. So,
I'm not quite sure if I've -- feel like [laughs].
>> Howard Bauchner: It's hard to give precise
numbers. Just one other -- one other epidemiology
question or two. Is smoking protective? When
you look at the literature, is smoking protective?
Do either of you think smoking is protective
and asthma is protective?
>> Derek C. Angus: So, I was actually -- I
was thinking you were going to ask me the
same question that you asked Maurizio. [Laughter].
So, I was thinking of generally about do we
not know, yet? And I think that the only thing
that we know very clearly is that the frail,
elderly when they get infected really struggle.
I think that there's still a lot of questions
about all the other frail groups. Who exactly
is vulnerable other than the elderly? We definitely
seen in many Western countries that folks
from the minority groups and folks who are
from, poor folks who are poorer appear to
have a disproportionate burden. But the mechanisms
for that are still not clear, unquestionably.
A big piece of it could be that they get different
access to the healthcare system in the first
place. But teasing out the relative contribution
of underlying heart failure, COPD, even the
route of contribution, for example, patients
who are -- who have cancer. It's still not
clear. We still don't really know the mechanism
by which relative immunosuppression would
increase your risk or not. Some of that is
because we still don't have good denominator
data. So, it's really hard to work out whether
the frequency rate per 100,000 is genuinely
higher in those groups. And we still haven't
teased out a genetic component, yet, which
could well be partially explaining why we
sometimes hear about people that seem seemingly
healthy before they get sick, who then get
very sick. Was there some genetic reason for
it? We don't really have answers to any of
that. So, on the one hand, the epidemiology
feels relatively stable. And there's a relatively
consistent narrative. But on the other hand,
I would actually say, there's a lot that we
have still not nailed including smoking.
>> Howard Bauchner: Yes.
>> Derek C. Angus: I don't -- the answer to
smoking.
>> Maurizio Cecconi: Well, I'm glad they asked
you that question before me. [Laughter]. Because
I also don't have the answer to that. What
I would just add to this is that in the beginning,
because these were so surprising and overwhelming
for everyone, and everyone was trying to help.
We had a lot of anecdotal evidence of people
saying, I've not seen my cancer patients getting
sick. I've not seen my asthma patient getting
sick. But then when you start to see bigger
[inaudible] was an example. We all thought
maybe there would be, you know, protection
or a race with it. But actually, we started
to see very large series. The effect was not
there. I do wonder whether some of the observations
around smoking and asthma and other comorbidities
actually are going to follow in a similar
way when we actually started on a much larger
population. So, I will say, I agree with Derek.
To me, I don't know yet which one is a risk
factor that makes you more susceptible to
get the virus but certainly age and frailty
is something that if you do get the virus,
you are very likely to do worse than others.
For instance, I also see the same thing in
age. In Italy, we've unfortunately, something
like 30,000 deaths. If you split the age,
you know, in a very gross way, like more than
15 less than 50, less than 50 years of age,
I think, we have roughly 400 that's in the
old country. I fact, they seem to count towards
[inaudible] care. Of both deaths, we have
all the other deaths.
>> Derek C. Angus: Yes. So, --
>> Howard Bauchner: Well, wait. I want to
-- I've got to go to the second question.
We'll be here for two hours. Okay.
>> Derek C. Angus: Could I just add a little
point?
>> Howard Bauchner: A little point. [Laughter].
>> Derek C. Angus: [Inaudible] two pieces.
So, the in Pennsylvania there have been more
deaths over 100 than there have under 50.
>> Howard Bauchner: Okay. mm-hmm
>> Derek C. Angus: The second thing is even
the elderly, we don't really know why, so
for example, if it's immunosenescence, then
that might be true for anyone over the age
of 65. If it's not immunosenescence, then
in countries with a lower mean age rate, because
of greater acquisition of comorbidity earlier,
then the consequences of being elderly may
be borne by people who are relatively younger,
for example [inaudible]. And that's also [inaudible].
>> Howard Bauchner: Well, now I want to go
to a subject that is complicated and controversial.
So, I think many of the listeners in critical
care know we published a paper by two legends,
true legends, John Marini and Luciano Gattinoni
entitled Management of COVID-19, Respiratory
Distress. It's attracted quite a bit of attention
and I would say some controversy. And Derek
warned me when we accepted it that, you know,
people would have mixed feelings about it.
Maurizio, you probably have cared for as many
patients with COVID-19 as virtually any critical
care physician in the world, certainly as
many. Where are we on respiratory support?
High-flow oxygen, prone positioning, preventing
intubation? Is early intubation better than
late intubation? So, you may want to prevent
intubation but do you wait too late? You've
been at it for three months, what do you think
you now know?
>> Maurizio Cecconi: So, I would say that
after three months I still know that I don't
know a lot of things about this virus. And
therefore, because I didn't know a lot of
things about this virus and it was, you know,
new to us. But we were used to managing acute
respiratory failure, ARDS, and you know severe
respiratory failure. With my team, actually,
we decided to have a very reproducible, very
simple approach. So, we thought we do behave
as if we have one patient in front of us,
not as if we have 107 patients, which is what
happened in my unit at some point. So, I would
say, I don't think I change my practice in
terms of the management of acute respiratory
failure. So, people often ask me, so, was
[inaudible] ventilation a contraindication
to this patient? I don't think it was because
I don't think it was even before this. What
the contraindication is if patients are getting
tired. If you get the feeling that they're
getting tired, I would not delay an intubation
there. But, again, in the way that we manage
these patient, there is one thing that is
true, I would say, and that was apparent pattern
from the after you manage the first 10, 15
cases, you realize there is a pattern in these
patients. And so, very often they are hypoxemic.
But actually, carbon dioxide clearance is
not a problem. And they seem to have, not
all of them, but a majority of them, seem
to have reasonably good compliance. So, when
you do intubate them, you often find that
you don't need a lot of pressure to ventilate
these lines. Actually, that could be counterproductive.
But I did find some patients that had a low
compliance compared to others. So, what I
would say is that I found my average group
of patients compared to the average ARDS before
move to a slightly higher compliance group.
But I didn't like to use the same PEEP in
every patient. I still tried to individualized
PEEP and look at both the respiratory system.
And my passion has always been with [inaudible]
and looking at hemodynamics component of what
I was seeing in front of my eyes, patient
from patient. So, bottom line is I didn't
change my practice on CPAP and NIV but I decided
not to drug patients on NIV as I was not doing
before. And when we intubated these patient
we still tried to apply protective line strategies.
Protective line strategies doesn't mean that
you use the same strategy for everyone. You
use the same approach for everyone. The patients
may get different levels of PEEP, different
levels of pressure support, pressure control
ventilation, or volume control ventilation,
which we use quite a lot in the beginning.
>> Howard Bauchner: Prone positioning prior
to intubation?
>> Maurizio Cecconi: Yes. Now, we didn't have
experience in my institution with prone position
prior to intubation. I know that you published
a paper from one of the groups [inaudible]
hospitals here. A few colleagues actually
told me that they use it a lot. I was probably
lucky to be in an area that got a lot of admissions
but I was able to support the other hospitals
rather than being overwhelmed by the admissions
of my emergency department. So, I never had
to use rescue strategies in the ward. I always
had enough space to escalate to intensive
care if I thought it was a problem for the
patient. So, we didn't use prone positioning
in our awake patients. I know that many people
are doing that. They do respond pretty well
to prone in these patients. So, you do see
that the reasoning [inaudible] being NPL too
after your prone. What I do not know is because
we've never had experience of awake prone
before, is if these transits increase [inaudible]
physiological variables [inaudible] prone
when you're awake is then translated into
a better outcome long term? I think no one
knows that because we didn't have time to
do a trial [inaudible] to see really if the
improvement in numbers that you see a bit
side is translated also into patients centered
outcomes later on.
>> Howard Bauchner: Right. The two papers
we published were research letters and I think
both of them comment that it's nice to have
short term gain but what you really want to
look at is what does it mean in terms of 28-day
mortality or 60-day mortality. Derek, you've
seen more patients now over the last month
or six weeks. What's your sense of kind of
the approach to respiratory support?
>> Derek C. Angus: Well, so, I still think
that our experience is dwarfed by that of
Maurizio's. And, so, I really have -- it's
hard for me to think that I have anything
to add. I think reflecting not only what we've
seen in Pittsburgh but what we've heard from
around the world. It's not clear to me that
people would have even tried proning prior
to intubation had it not been because they
were under extreme circumstance. The very
fact that it's become an option is definitely
been -- necessity being the mother of invention.
But it seems plausible that there's definitely
a role for much more aggressive pre-intubation
management, including for example, if you're
using NIV and then you can safely prone, you
maybe avoid intubating people. I totally get
the long-term consequences are unclear. On
the other hand, intubating someone can be
hazardous for their health. So, do we need
an actual RCT of trying to do NIV with proning
as a legitimate strategy? It sort of feels
like it would be valuable but it also feels
like it's quite a hard trial to even bluff.
I think I would broadly say that there's been
this learned conventional wisdom to be more
aggressive in the use of non-invasive strategies,
[inaudible] broadly, in the early management
of these patients than we would necessarily
have done traditionally. And to the extent
that there's some wisdom in the masses, it
seems reasonable. Beyond that --
>> Maurizio Cecconi: To be honest, I think
--
>> Derek C. Angus: Maurizio nailed all the
--
>> Maurizio Cecconi: No, I just wanted to
add that I suspect that those depend on what
you're most familiar with. I think one of
the messages is that we decided to use with
my team and we were trying to say, let's try
to do what we're most familiar with. And for
instance, in Italy there is a big tradition,
long tradition of helmet CPAP. For instance,
when I was in the UK, [inaudible] are very
rarely used. And I kind of learned it here
in the last three years that [inaudible] been
here. We use quite a bit of it and, yet, my
colleagues from the region, if I say the word
non-invasive ventilation, they would tell
me, you're wrong. It's not a ventilation.
It's just a CPAP. Because by the time you're
under [inaudible] and you ventilate, probably
is the time to intubate. And I guess, that's
being our experience here. We try to put a
bit of positive pressure with helmet CPAP.
We managed, probably, an equal number of beds
for CPAP or non-invasive ventilation compared
to what we manage [inaudible] invasive mechanical
ventilation. So, we use quite a lot of it.
We are actually analyzing the data for some
of this, which is being [inaudible] now we're
going to see what the outcomes are. But I
can tell you that given in my institution
we have some patients that completely recovered
without going through invasive mechanical
ventilation and just spending days on CPAP
and they were discharged home.
>> Derek C. Angus: The only other thing I
would say is, there is definitely quite a
lot of reports of people who are sick enough
to be admitted. They're not initially terribly
hypoxemic. But when they develop hypoxemia,
it can be very rapid. And so, if you admit
someone and you manage them non-invasively
and you put them in a setting where there
isn't rapid access to someone who is facile
in intubation, it is that's definitely potentially
risky. So, the one caveat about aggressive
use of non-invasive ventilation is to do it
in a setting where if nonetheless the patient
does deteriorate, you still have rapid access
to someone who can secure [inaudible] and
put them on invasive ventilation.
>> Maurizio Cecconi: I completely agree. And
indeed, for us, probably one of the biggest
challenges where we were really constrained
on the number of beds for invasive mechanical
ventilation was how do you set up non-invasive
ventilation beds in a safe way? So, that [inaudible]
miss the deterioration? You don't want to
be called for a [inaudible] you have to go
there much earlier and escalate much earlier.
So, that was a -- the biggest challenge was
probably how do you bring intensive care out
of the wards of intensive care?
>> Howard Bauchner: Now, we're going to turn
to the next two areas. They're related and
they're really complicated in the sense that
are there phenotypes and should phenotypes
drive therapy? Now, for people who are -- I
talk to Derek every day, either by email or
phone. And I will give you a partial list
of what's crossed my desk as treatment. Ozone
therapy, vitamin D, lysotrophic agents, diet
manipulation, thymus regeneration, hyperpyrexia,
toesies [phonetic spelling], cyclosporin,
heparin, Icatibant, zinc and AZT, plasma exchange,
low-dose radiation, combination drugs. Did
we launch the RCTs before we knew the phenotype?
And perhaps the reason Remdesivir hasn't been
so successful is you don't want to use it
on everyone? We just published a paper on
convalescent plasma with a 10% reduction in
mortality. Derek knows I was going to ask
this question. Maurizio, I sent you this question.
Thrombosis and heparin. Are there phenotypes
that we've missed and do we need to marry
treatment to these phenotypes? We'll go back
and forth on this one because I could read
another list of 20 more ideas about treatment.
Maurizio?
>> Maurizio Cecconi: Derek can go first if
you want.
>> Howard Bauchner: [Laughter]. Alright, Derek,
you go first on this one.
[ Laughter ]
>> Derek C. Angus: Well, anyone who knows
me, knows that, of course, there's subsets
of patients. And it's highly likely that therapies
might have broad effects but some of them
not -- not only might the relative risk be
reduced differentially -- sorry, not only
might the absolute risk vary by some group
but the relative risk might vary. So, there
could be true heterogeneity of treatment effect.
And indeed, some therapies might be actively
harmful in some groups. You put heparin on
the list. I think every one is very worried
that some important subset of patients have
some set of fairly serious endotheliitis,
endotheliopathy. And it may well be that nothing
short of therapeutic anticoagulation will
save them. But therapeutic anticoagulation
has a known side effect profile. And so, it
might be quite hazardous to put every patient
on therapeutic anticoagulation. And an important
subset may see no benefit from that degree.
So, right off the bat, I think people who
want to study anticoagulation might restrict
it only to those who are the sickest patients.
Those are the sickest patients with at least
some signs that there is an important component
of this endotheliopathy. So, for example,
maybe you should only give it to patients
with elevated D-dimmers, elevated D-dimmers
and a bad shunt suggesting maybe V-Q mismatch
and so on. I think tied to this you were asking,
should we have waited before starting the
trials?
>> Howard Bauchner: Right.
>> Derek C. Angus: No, no, no. [Laughter].
But it does mean that it's not enough to do
one trial. So, in other words, you could start
a trial. You could have a design like an adaptive
platform trial that actually tries to learn
by phenotype over time. Or you could just
make a commitment to doing sequential trials
where a big trial might run and there might
be a negative effect. A neutral effect overall
but a promising subgroup, then you should
go and test in the subgroup. Now, you still
need to try to be safe so you wouldn't want
to roll out in thousands of patients of therapy
with a known safety concern in a subgroup
that you have poor rationale for expecting
benefits. But with those caveats in place,
I think you start with what you have and then
you refine over time. And that's what we did,
admittedly over decades. But that's what we
did with acute myocardial infarction, STEMIs,
nonSTEMIs were all thrown together. You learn
over time it's just a compressed time scale
makes it look like there's more room for sort
of decisional regret. Because we can still
remember the trial we began 2 1/2 months ago.
But this phenotypic variation should not have
stopped us from launching trials as soon as
possible.
>> Howard Bauchner: Before -- Maruizio, before
you comment, Derek knew I was going to ask
him this question. Are there other phenotypes
that you think are merging, you know, this
thrombosis, this inflammatory cascade? Are
there others that you think are merging or
we're just not smart enough to know?
>> Derek C. Angus: Are you asking me?
>> Howard Bauchner: I'm asking you, Derek.
Now, we'll go to Maurizio. No, no, no. because
you went --
>> Derek C. Angus: It is. I'll give you --
>> Howard Bauchner: Because we went to adaptive
design. But before you get to adaptive designs,
I mean, you know, I've cyclosporin on this
list. I have low-dose radiation on the list.
>> Derek C. Angus: No, I'll give you one immediately.
Viruses make you lymphopenic. Everyone talks
about the cytokine [phonetic spelling] storm
and wants to blunt DNA immunity. But maybe
there's an important subset of patients in
whom the biggest problem is that they need
support for their adaptive immune system.
Maybe there's a subset of patients in whom
we should be boosting immunity, not suppressing
immunity. Just, again, by the way, don't try
this at home. [Laughter]. I'm only suggesting
this as a hypothesis where they have testing.
Nothing I'm saying here suggests people should
go out and just start these treatments. I'm
thinking about this inside the context of
randomized trials.
>> Howard Bauchner: Maurizio, do you have
a sense, I mean, you've seen so many patients.
Are there different phenotypes?
>> Maurizio Cecconi: I think there are different
phenotypes. And I think that's what people
try to do, I mean, if we have phenotypes,
you try to classify a disease and a group
of disease, where you find common patterns
of, you know, [inaudible] and D-dimmers and
so on. I think that's what people have tried
to do quite a lot here. I'll come back to
the thing that, you know, we often talk about
preparedness, about the pandemic. I think
there is a big concept about [inaudible] preparedness,
at the least, probably in Europe. I don't
think we were as ready as we could have been.
But come back to the phenotypes, I think one
of the problems that you have, you may recognize
a pattern, interfering with that pattern and
there's been a lot of views of compassionate
use of drugs. I know off-label drugs. It's
a big jump between association in [inaudible]
not only that a lot of the so-called phenotypes,
they don't even come from large series of
patients. They often came from anecdotal evidence
and then this evidence, anecdotal evidence
they started to, you know, to become experts
[inaudible] about people with cytokine release
syndrome, which, again, you know, we had some
little evidence about it. We don't really
know if it is a common pattern in a lot of
these patients. So, I've seen a big rush to
treat. I'm sure every doctor tried to do their
best. I don't think anyone tried drugs to
harm patients. However, I completely agree
with what Derek was saying. Until you don't
really know the mechanisms very well, with
a good observations and also then with trials.
We need to know if what we're doing not only
lacks efficacy, which is a problem, but maybe
brings harm. And, you know, [inaudible] harm,
I think, should be our first drug. In my intensive
care, for instance, we decided not to start
adjunctive therapy pretty much in any patient.
So, we didn't start anything new. We had a
lot of patients coming with liberal drugs
from the wards and maybe [inaudible] from
the community because there was a wide use
of hydroxychloroquine, as in for instance
in many other countries. Probably the only
therapy that I decided in selected cases to
use is being steroids. Steroids are also controversial
in viral disease. But I took an approach that
if I didn't know I would try not to use something
and just tried to do as best supportive therapy.
>> Howard Bauchner: Maurizo, do you think,
I mean, the Remdesivir trials are interesting,
one negative, one positive in the sense of
shortened ICU day, kind of a 3% reduction
in mortality. Our convalescent titer paper
suggests in seriously ill, not critically
ill, potentially a 10- to 15% absolute reduction
in mortality. Is it going to take more than
one drug? You mentioned steroids, that's a
question that came up. Is it convalescent
plasma and steroids? Is it toesie and steroids?
Is it -- to really reduce mortality, is it
going to be a combination of some sort?
>> Maurizio Cecconi: It's going to be a combination
of some sort. But, again, I'm an intensiveness.
I like to talk about intensive care. I really
believe that, you know, good evidence based
seen for supportive therapy doesn't cure the
disease but by [inaudible] time avoiding causing
harm with the organ support that we do. And
that can, you know, can impact significantly,
I think, cause of mortality. But probably
for something until we don't have a vaccine,
I don't really believe that we will find the
magic bullet. And that's why it's going to
be even more important, doing proper trials,
I think. I don't think just with observations
and without proper controls you can realistically
spot the difference of 3- 4% in your practice.
You will just believe what you want to believe.
So, I guess, a combination of treatments probably
is one of the things that we have to explore.
I guess the nice things about the Remdesivir
trial and the convalescent plasma trial is
two things. One, first of all that we manage
to get a trial of 1,000 patients, which is
a pretty impressive effort during a pandemic.
Even though the primary outcome was changed,
but there are good explanations for which
they did that. So, I actually do believe the
data, I think, it's a good trial. It doesn't
-- it's not going to be a game changer for
everything. But I think it's a good trial.
And the convalescent plasma trial that you
published recently, I think, is also a nice
one because at least it's showing it was not
made for that, but at least it's showing that
probably the treatment is relatively safe.
You have very few side effects there. And
if you look at the secondary outcomes, even
if they were not significant, they were all
moved towards some possible benefits for plasma,
at least in the severe cases, not for the
life-threatening ones. So, I think, [inaudible].
And that's, unfortunately, that's the thing
for me and Derek. We work in intensive care.
We are at the end of the process. Very often
what we can do is really support the organs
and avoid doing extra damage. But actually,
if you really believe that therapy should
stop the disease or should stop the progression
of the disease, I suspect they will have to
be given earlier, probably. I suspect when
you're in intensive care, may be a little
bit late.
>> Howard Bauchner: Derek, do you think it's
some form of two drugs? Is it earlier treatment
with some drug regimen?
>> Derek C. Angus: Right. So, I think that
antivirals have the best chance if given very
early. And effective antiviral stops viral
replication, essentially turns COVID into
sepsis. If the patient is already sick and
still doing viral replication but now has
system organ failure, if we arrest viral replication,
then we've essentially got a patient who is
like a patient with bacterial sepsis for whom
we have an antibiotic that kills the bacterium.
And having an antibiotic that kills the bacterium
does not cure you of sepsis. So, I think that
something like Remdesivir could totally shorten
the course just -- it's quite plausible. The
findings in the New England are quite believable.
But shortening the course is not the same
as completely curing people. And for that,
almost certainly, we'll still need to think
about all the, essentially the same chase
for effective supportive and directed therapy
that we chase in sepsis. The right kinds of
organ dysfunction support and, ultimately,
the Holy Grail would be doing optimal support
of the host immune response and not just immune
response but all the secondary cascades. So,
for example, if someone already has endotheliopathy
and has already got extensive microvascular
coagulation, eventually that might undergo
a vascular remodeling. But simply stopping
the virus from replicating doesn't immediately
remove from that person the threat to life
that's being engendered by this sort of distributive
microvascular coagulation in their pulmonary
vasculature and so on.
>> Howard Bauchner: Now, my understanding
is 17,000 people in the U.S. have gotten convalescent
plasma, more than have gotten Remdesivir,
actually. Because it's so readily available.
What's your sense of that as a treatment?
>> Derek C. Angus: Yes.
>> Howard Bauchner: The study we published
was small.
>> Derek C. Angus: Yes, so, it's not the first
study. [Laughs]. As you heard me say before.
JAMA published a study on convalescent serum
in 1918 for the Spanish flu. So, we've been
banging on this nail for a long time. There's
-- the rationale is really strong. Again,
the issue is when should it be given. If it's
adequately safe and adequately plentiful,
then one would want to move it earlier in
the course. And one would, ultimately, think
that convalescent serum, of course, would
be replaced by synthetic antibodies. It could
be more targeted, smaller total dose, and
if adequately safe could almost be given as
a sort of prophylaxis for high risk groups
and so on, essentially, wide-spread, passive
immunization. And that's sort of the end game,
I think, for this class of therapies. In this
intermediate time period before we have widespread
effective synthetic antibodies, I think convalescent
plasma is intriguing. However, what's the
fidelity of the product from person to person,
or from aliquot to aliquot? That'll be tricky
to know. And when is the best time to use
it? Should you use it in ICU patients or should
you move it upstream and use it in nursing
homes? I think there's a lot to be said for
trying, even with convalescent serum, to try
to move it earlier in the process.
>> Howard Bauchner: Maurizio, you've seen
an enormous number of patients who've been
discharged. And I appreciate all the complications
of where they go, and homecare. Does the morbidity
associated with COVID-19, following being
in the ICU look different to you than any
other frail, elderly individual who is in
the ICU and is either intubated or not? Does
it look different to you? Do they need a different
type of post-ICU care?
>> Maurizio Cecconi: It's a very good question.
And it's probably a bit earlier to tell you
what's going to happen to this patient. No
healthcare system has seen this amount of
pneumonia all at the same time. So, the burden
even on rehabilitation and post-intensive
care syndrome is going to be massive. We are
doing some follow ups in my hospital. And
what we are seeing now are the first survivors
that come back. I'm going to give a very biased
answer in the sense that these people are
able to come back to follow up and that's
already a good thing. Because they can either
be in a car with their family and so on. We,
anecdotally, we are surprised to see how much
some of them have been able to recover in
old age. However, I can also tell you that
probably the last 10%, 10- to 15% of patients
after the pandemic peak have been very long
term [inaudible] patients in our intensive
care unit. And I even know about some young
patients that are now recovering but they
had [inaudible] for, you know, two months.
And is going to be a very long process. And
if you speak with them, they'll still tell
you that they are fatigued. They are now investigated
by pneumologists in terms of, you know, fibrosis.
We are seeing some of the usual complications
like [inaudible]. So, the variety is so high
that I would expect significant burden also
in terms of what is follow up for this patient.
However, the nice thing is that we've seen
a significant group of patients that seem
to have made a full recovery. And some of
them even older patients in their 70s. They
are walking to our follow up clinic. We're
now investigating six minutes walking test
and we're trying to see what they're doing.
And some of them, they had a good recovery.
But there is certainly, and I cannot quantify
what [inaudible] is, but with the huge number
of patients that we treated, it's going to
be an absolute big number. There certainly
is a group of patients that require a lot
of help to try to go back to a reasonable
quality of life and we don't know if they're
going to have permanent damage to their lungs.
>> Howard Bauchner: Derek, a sense of post-COVID
care needs, yet? A sense of whether these
patients need more or less than any other
patient being discharged from the ICU who
is older?
>> Derek C. Angus: Yes, so, I think we really
don't know, yet. But there's lots of reason
to have some concern that this would be sort
of a nasty bite in the tail of this epidemic.
I think -- we know in the past that the amount
of respiratory damage from severe ARDS is
relatively speaking comparatively mild. The
patients who survive sometimes have a few,
sort of, restrictive function abnormalities.
But the more striking, overwhelming picture
is usually one of general physical deconditioning
and also a wide array of mental health concerns.
And I have two worries about this. One the
physical health rehabilitation, regaining,
sort of, motor skills, regaining girdle strength
for getting in and out of chairs. That involves
intensive physical therapy rehab. And one
has to worry about how much of the physical
therapy workforce with somewhat furloughed
or unable to engage in usual services because
there was such destruction to healthcare systems
at a time when it might have been particular
vital to be doing rehab. And then by extension,
similarly, I'm worried about the quality of
mental health support for, especially since,
if anything, being sick with COVID, was probably
worse than being sick with other ICU illnesses.
Patients had protracted periods in the ICU
totally alone, where they couldn't access
family members and so on. And so, I wouldn't
be surprised if some of the mental health
sequelae from protracted COVID disease manifests
at a higher incidence and a higher burden
than it does in general ICU populations.
>> Maurizio Cecconi: I think you're right.
>> Howard Bauchner: The same two questions
to the two of you to finish. We'll start with
you Maurizio. The two or three surprises,
this pandemic, from a critical care standpoint.
And the two or three scientific questions
that we need to answer. And then, Derek, the
same for you. The two or three surprises and
the two or three most important scientific
question. Maurizio?
>> Maurizio Cecconi: Well, I guess, the surprise
was finding out where the cluster, I mean
the region, that was a big surprise. And I
guess that was also with hindsight, really
made me realize how much we underestimated
what was happening in China. And also, it
made me realize our systems -- I worked [inaudible]
and I worked in Italy. Our system, they are
not really made to work on a [inaudible] buffer
of resources to be used during a pandemic.
There are always not to the limits but, you
know, our capacity is 90- to 95% of ICU capacity
in winter. We are not rated to manage a pandemic.
I think that's been clear everywhere. And
I think that's the biggest surprise. How many
sick patients can come at once if you have
a disease like this coming. That was really
surprising and kind of scary, actually, in
the beginning. I would say the initial wave
that we saw was really something that we thought
that if this does not peak, we don't know
where we're going to go next. The other thing
that caught us a little bit by surprise, I
would say, I don't think we were ready to
do also research properly in a pandemic. In
the sense that what Derek is leading some
of these adaptive trial designs, like [inaudible]
and so on. I wish we had good infrastructure
in place to start using it, you know, almost
after a week, after two weeks. Now, we're
now in the process of doing that. And I would
say these are the two things that caught me
by surprise. In terms of things that have
been a nice surprise has really been the resilience
of people working together for a common goal.
During those six, seven weeks of the peak
in [inaudible], I mean, I'm so proud of my
team but I'm really so proud of everyone.
And I'm so proud of all my colleagues around
the world. I spoke with people in different
countries and I know I hear exactly the same
stories everywhere, is how much we pulled
together for a common goal, which was really
trying to give intensive care to whoever need
and benefit intensive care. And I would say
probably that made me realize that we spent
too much time talking about ventilators, too
much time talking about machines and [inaudible]
and less time about people. If there is one
key lesson for me, and with the European Society
of Intensive Care Medicine now we are collaborating
with the European Commission, with the European
Union, to try to get ready for a second wave,
if there is a second wave or for something
else in the future. There is a clear need
to try to bring harmonization of competencies,
I would say, and also maybe to bring competence
where they're most needed. There is one common
thing in this pandemic, if you've noticed.
Clusters that don't occur around the world
at the same time. [Inaudible] was one and
then a few weeks later there was another one.
What we've done in many countries was creating
some empty facilities just in case but then
we didn't have the doctors and nurses to put
in these facilities. I would have kind of
envisioned to have a healthcare army that
could be moved from place to place. Rather
than creating empty spaces, why don't we move
the competencies where they're needed? Everyone
was trying to get new ventilators to be there
just in case. Probably what we needed was
to move competencies from intensive care clinicians,
nurses, and [inaudible] care professionals
to where they were needed. And I think, that
again, was a mindset that we didn't have.
And I would like to have it for a second wave
if something like this happens again. I hope
it doesn't happen. But I wouldn't like to
be surprised twice by something like this.
>> Howard Bauchner: Derek, the scientific
questions that, you know, linger in your mind?
>> Derek C. Angus: Yes, so, Maurizio said
-- I mean, I agree with everything he said.
I guess, I would start by taking up with his
last point. It's really fascinating the patchiness.
So, not only did they not happen at the same
time but Rome never behaved the way Milan
did. And as we all watched New York, and it
was so awful, we really felt Boston, San Francisco,
Seattle, and then New Orleans, and you know,
that they would all follow a similar pattern.
And some of it, maybe, school closings, and
social distancing began a little bit earlier.
But it's hard to explain why some cities just
have a terrible disease outbreak and others
don't. And some of it could be the actions
we take but there's still a lot that we don't
understand about that. As far as scientific
questions about -- You probably want us to
talk about scientific questions for ICU patients
and get right into the syndrome of the disease.
>> Howard Bauchner: That's okay.
>> Derek C. Angus: And yet, it's actually
-- I feel like with Remdesivir we've just
created a viral sepsis. And I almost feel
like, for me, the pressure of solving viral
sepsis is no more prescient than the pressure
of solving sepsis. I actually feel like once
we have effective antiviral, in a way for
me, the biggest danger is that the only treatment
we're using right now is massive social distancing.
And as you've heard me talk about before,
the consequences of the treatment may be worse
or as bad as, if not worse, than the disease.
And so, for me, a scientific agenda would
be how can we truly protect the vulnerable?
How can we protect patients in nursing homes
so that we can really open the rest of the
economy, not have our children not be in school,
not have people losing their jobs? But get
on with normal life. Because this social distancing,
we as an intensive care community, we needed
that as a short-term fix to avoid a complete
unmitigated disaster of ICUs being completely
overrun. But ICUs can be run, they just can't
be overrun. We can manage a lot of COVID while
the rest of society carries on. So, I would
-- I think the most important scientific agenda
is just the strategy for protecting the frail
and managing like a surveillance system so
that homo sapiens can get back to being homo
sapiens.
>> Maurizio Cecconi: Yes. I think it's a very
valid point. We often talk about precision
medicine and, you know, the [inaudible] of,
you know, a kind of precision public health
measures, we've not really applied properly.
You're right. Everyone was doing social distancing
in the same way. And I completely agree with
what you were saying at the beginning. If
you look at case fatality rate in different
countries, certainly, countries that have
done better in protecting the vulnerable,
at a much less burden on the healthcare system,
and good for patients to have less death,
as well.
>> Howard Bauchner: So, Maurizio, you -- we
did the live stream on March 13. And it almost
seems, almost like a different decade ago.
And you in some fashion that I've struggled
to understand announced to the world that
we didn't quite know what was happening, or
was going to happen. And that we needed to
be prepared in a different way. This was based
upon what was then a week or two of experience.
And I've said this before, you, along with
Dr. Fauci in the United States -- Have crystalized
more than any other two people around the
world this pandemic. Somehow the earnestness
and the goodness and the generosity of being
a physician. I can't emphasize that enough.
I don't think I've ever been prouder of my
profession as I have been in the last three
months. And, Derek, you know how highly I
think of you as a friend and a colleague.
And you've made me kind of an honorary ICU
member. I just don't ever want to have to
take care of a patient in an ICU, nor do patients
want that. But I can't think of two people
who could better represent a discipline. This
is Howard Bauchner, Editor and Chief of JAMA.
And I've been talking with Maurizio Cecconi,
President-elect of ESICM, and Derek Angus,
our Associate Editor and Endowed Professor
at UPM -- at UPMC. Maurizio, thank you for
your time today. I'm glad you can see your
children, again. And Derek, thank you for
your time today. And I know you are already
seeing your children today. Bye bye.
>> Maurizio Cecconi: Thank you. Bye, bye,
everyone.
>> Derek C. Angus: Thank you. Bye, bye.
