Hey, everybody. Welcome back to Palm Peeps. I'm
excited today to be back with Luke Hedrick
and doing another rapid fire journal club. We
had a lot of fun discussing
ARDS trials, a bunch of landmark trials, in
ILD, I think was the last one we
talked about. And we have, another great article
to discuss today. Luke, how are you
doing? Hey, Dave. I'm good. I'm happy to
be back. It's been a minute, but I
think this will be a nice addition to
the journal club series.
Yeah. And without further ado, we don't have
to build up the suspense too much more.
What trial are we gonna talk about today?
Yeah. So today we're gonna be talking about
the missed two trial, which was published in
the new England journal in 2011.
Great. Yeah. I think that this is a
real,
truly practice defining trial. We've talked about a
lot that really shaped our practice and we'll
dive into the details of what, but I
think that this is one where very specifically
the protocol and the trial has become a
real standard of care. Let's talk about what's
going on.
So we know that there's gonna be some
background since this is missed two and there
was a missed one trial. So why don't
you tell us what the background was leading
up into this trial? Yeah.
So we know that infections in the plural
space are common and morbid
and often require surgical intervention
to definitively manage.
And unfortunately,
antibiotics and chest tube drainage alone often fail.
The MIST-one trial, which was published in the
New England Journal in 02/2005,
studied intrapleural streptokinase,
and unfortunately that showed no benefit.
And so here, the MIS two trial was
a study of intrapleural tPA and DNase to
try to ease drainage of these infected effusions
by breaking down septations
and thinning the pleural fluid itself.
Yeah, that's great. We've talked about complex pleural
effusions
previously on the show. We've talked about infected
pleural spaces and empyema previously.
This is a common problem that every pulmonologist
is going to run into that you might
see in the ICU, but you also might
see in the clinic and the floor. And
it's a really interesting one because it can
affect people of all ages. I've definitely seen
immunosuppressed
people with really badly infected portal spaces, but
I've also seen the young, really totally healthy
who person who had pneumonia,
maybe got therapy or maybe honestly muscled through
and then developed a severe pleural infection. And
so having guidance of how to manage it
is super helpful. And we're really thinking about
enzymatic therapy. I call this enzymatic therapy as
its combination.
Intrapleural tPA
less, more, less of a pure enzyme than
DNA ACE. The combination of them of trying
to break down septations,
thin the pleural fluid collection, and drain it
appropriately
is what can help make these people better.
So how what was the study? They wanted
to answer this question a little bit more
thoroughly than and with a different protocol than
in the first trial. So what study design
did they come up with?
Yeah. So the
this study here was a double blind, double
dummy, two by two factorial
RCT that was run at 11 different hospitals
in The UK
from December 2005 to November 2008.
And by double dummy, what I mean is
that there was actually a sham placebo for
each of the study drugs, which is pretty
interesting.
Yeah, it is really interesting. It really helps
add to the validity of study that you're
giving a placebo intervention. And these are very
physical to give a placebo because you're thinking
about going and instilling something into the chest
tube. So really nice that we know
everybody's really blind. So that's the patient, the
treaters, the investigators.
One thing that's really important with these infected
pleural space infections is that outcome that we're
looking for, because
we're talking about a different set of outcomes
than we may be in our classic ICU
trials or our classic chronic pulmonary disease trials.
So what were the primary and secondary outcomes
that they wanted to, have some insights into?
Yeah, the primary outcome here is.
A little bit wordy, but it's the change
in the percent of the hemithorax.
That's taken up by the effusion on chest
x-ray
at day seven compared to day one, which
is like a roundabout way of saying
how much do we think we got out.
We're not looking at just milliliters of fluid,
but relative to
that patient's own imaging.
And then the key secondary outcomes that they
looked at were referral to surgery,
hospital length of stay,
all cause three month and twelve month mortality,
and then safety, any kind of adverse effects
from instilling TPA and DNAs into the plural
space.
Totally. And I like this combination of outcomes
because the primary outcome really gives us that
functional, how did we do with this therapy?
Did it have the intended physiologic effect
that is represented by a radiographic finding that
we were shooting for by giving this therapy?
And then all of the secondary outcomes are
the key ones that we care about for
these patients. And I'll make a special note
about the referral referral for surgery. This is
often the endpoint of interest in these plural
interventions for effective plural spaces because we know
that there is a surgical option that can
be done. You can always go in and
open and clear out the the plural space,
but you also wanna see if you can
get away without doing that to decrease morbidity
for the patients.
All right. So we know what we're gonna
be thinking about. Now we should think about
who these patients are. So what were the,
key inclusion criteria that we have for this
study?
Yeah. So the inclusion and exclusion criteria, I
think we're
aiming to cast a pretty broad net. So
in terms of inclusion criteria,
anyone with clinical evidence of infection that was
assessed by the recruiting physician, so fever, CRP,
white blood cell count.
And then also had pleural fluid with any
of grossly purulent drainage,
a positive fluid culture or Gram stain, or
a pH of less than 7.2. Any of
those would get you included in the trial.
And then in terms of exclusion, they were
aiming to exclude people with increased bleeding risk
because of the TPA that was being instilled
or people who they didn't think could re
expand the long after drainage, because that's really
what drives the benefit other than source control.
A lot of the benefit people get from
drainage of effusions is from re expanding the
lung. And so if you can't do that,
you're unlikely to really benefit from the trial
in the first place.
And so there's exclusion criteria where an age
18,
if you had previously gotten intrapleural
medications. So fibrinolytics,
DNase,
or both for an empyema, if you were
allergic to any of the study drugs,
if you had a coincidental stroke. And so
really they're thinking about the hemorrhage risk.
If you'd had major hemorrhage or trauma or
major surgery in the last five days, if
you'd had a previous pneumonectomy
on the infected side,
if you're pregnant or lactating and then the
kind of usual catchall
of expected survival less than three months from
something other than what caused the plural problem
in the first place.
Yeah, that's great. I think casting a broad
net, really capturing the people we wanna think
about. A few interesting notes on this. I
think that their inclusion about the plural fluid
studies,
it really shows us that in practice, there's
sometimes
less of a
clinical distinction between complex, para pneumonic infusion and
mpyema. The classic mpyema is that grossly purulent
fluid that comes out of your pleural drainage.
But then we also think about getting there
with a really low pH or positive cultures
or having a complex para pneumonic infusion that
meets one of those criteria. And this is
including all of those people because any of
those people are those that might need to
progress to surgery or might have really morbid
outcomes if we don't end up fixing this
pearl space. And then I'll just comment on
the exclusion.
There's a lot of debate about how much
bleeding risk there is by instilling tPA into
the pleural space. Obviously, some of this will
have systemic effects. That being said, you're not
giving IV tPA, but I think it's very
reasonable within a child to be conservative and
say that anybody who has an increased risk
of bleeding, we're gonna exclude just so we
have a true sense of how this intervention
can help people in the purest sense. And
so look, I always love that you summarize
who these people are for us and we
give a good blanket statement. So who, after
we've done this inclusion exclusion, who are we
really looking at?
Yeah. So who they ended up including
were middle aged, mostly male patients
with complicated plural effusions or empyemas
that occupied about one third to two fifths
of the hemithorax
with mostly small bore chest tubes for mostly
community acquired infections
and small bore here. They meant less than
15 French in size.
That's great. And I think this goes into
some of the previous existing data on, pleural
interventions and chest tube drainage. We've had prior
trials that show that small bore chest tubes
for complex paradigmatic effusion or empyemas are generally
just as effective as surgical chest tubes, even
though they have a smaller French caliber, whereas
opposed to say maybe like a hemothorax,
we're usually leaning a little bit more towards
a larger bore chest tube.
So that brings us to the intervention a
little bit. You already mentioned it's small bore
chest tubes, but I think the particulars of
how they were actually doing this intervention is
really important for how we could bring this
trial into practice. So what were the specifics
of the intervention?
Yeah, so this was a two by two
factorial trial. They took two ten patients and
then randomized them about one to one of
the following forearms. So either tPA and DNase,
which were ten milligrams and five milligrams,
tPA and placebo,
DNase and placebo, or double placebo.
And then those medications were both given twice
a day for three days
with clamping of the chest tube for an
hour after each dose in an attempt to
keep the drug on the pleural space and
let it act for a little bit. And
those drugs were not necessarily given at the
exact same time. And so a lot of
time at the bedside
instilling
medications and clamping tubes and then returning an
hour later to unclamp. Yeah.
And if you, I don't know if you've
done this in Belgium, but I definitely remember
doing it, going by putting the drug in,
coming back, opening up, putting another drug in,
or putting them in the combo. And I
think this guidance is really helpful for what
we do in practice, especially because we have
these arms that compare it to what if
you just used one drug. And we actually
have a whole other trial of just what
streptokinase did, as you mentioned, the missed one
that didn't have this effect. The devil is
in the details
and we really like to focus on trying
to do it exactly as they did in
their combined intervention arm.
So with that, what did they end up
finding? What were the outcomes that they ended
up seeing in the chart?
Yeah, I think in general, it's worth just
discussing the outcomes of that TPA and DNAs
arm and combination.
Because there was a highly significant interaction between
the two for the primary outcome and the
P of 0.002.
And so first thinking about efficacy,
that primary outcome of portal effusion size reduction
was significant. They found
a almost thirty percent reduction
in the space in the hemothorax that was
taken up at baseline
versus a 7.9%
reduction
of a fusion size with the placebo.
And interestingly, neither drug worked on their own
in terms of just draining the fluid out.
Yeah, that that's exactly really helpful.
To hear about how the arms that we
had of the single drugs really didn't give
us that same reduction. And so if
there ever was a time I remember one
time I had a patient where there was
gonna be a delay on the tPA, and
they said, could we just do the DNAs?
And obviously logistical things come into play, but
this really showed that it's this combination, the
synergistic effect that we're trying to capture.
So that's great. We know we achieved this
radiologic outcome that probably represents some physiologic significance.
But what about clinically meaningful outcomes for these
patients?
Yeah. And so that kind of leads us
to those key secondary outcomes.
The big one, I don't wanna bury the
lead too much here, was referral for surgery.
So in the tPA and DNase arm, only
four percent of patients were referred for surgery
versus sixteen percent in the placebo arm. So
an odds ratio of point one seven and
a p value of point o three.
The other secondary outcomes were generally neutral to
favorable. So the hospital length of stay when
you excluded a, like, nearly four hundred day
outlier in the placebo group favored the tPA
and DNAs. The mean length of stay was
just under twelve days versus seventeen days. And
then there was no mortality
difference. And overall seems like it
drained the fluid. People got out of the
hospital quicker and a good chunk of them
did not need surgery compared to the placebo
group. Yeah. Yeah. I think you said, as
you said, that's a lead. You're getting to
avoid surgery for a healthy chunk of people.
Sixteen percent is not a huge number, but
going down from sixteen to four percent has
a definitely a big impact. And I don't
think it's so surprising we didn't see a
mortality difference. We certainly have multiple treatments for
these infected pleural spaces. These patients were closely
monitored. So even the ones where it wasn't
working, I'm sure are getting very good care.
And so it makes sense that you might
not see that mortality, but hospital length of
stay, referral for surgery are certainly very clinically
significant.
And then you mentioned some of the concerns
with the exclusion criteria about safety. We aren't
doing an active drug therapy into this plural
space, so we always have to think about
adverse events for these patients. Was there any
difference or signal in the adverse events between
the groups?
No. I think just to be succinct with
it, there really was no difference in adverse
effects between the groups. There were six serious
events
across all four arms that were mostly related
to bleeding. There were some intrapleural bleeding, some
GI bleeding, and some hemoptysis.
And then the other adverse effects were made
up of some combination of discomfort or pain
with drug administration,
so the actual, like, flushing into the pleural
space. A couple of folks had some transient
mental status changes and then a rash. But
overall, there was no difference between the groups.
And so it seemed like it was pretty
well tolerated, all taken.
Yeah. That's great. Certainly, the pleural space is
very sensitive. There can always be pain with
this, but we always have to balance the
fact that there would be pain if you
had to have a surgical intervention as well.
And even the
All right. So we've talked about the outcomes.
We talked about who were the patients. It
seems like we have a really positive effect
in intervention.
What's our gross takeaway? What are we using
this trial to guide our practice about? Yeah.
I think the newspaper headline version of this
is that combination
intrapleural enzyme therapy with TPA and DNAs improves
drainage of infected pleural fluid and reduces the
need for surgery and hospital length of stay.
Yeah. Fantastic. I think a truly practice defining
trial, we're doing this every
maybe not every day, but every week or
month in the hospital for patients to have
this. And based on this trial, we should
really be looking for reasons to give patients
combination enzymatic therapy, as opposed for reasons for
them not to get it. Cause we think
this is a positive intervention that will have
good outcomes for their future lung health, their
lung expansion, and for not needing surgery to
get there.
All right. Thanks everybody for listening. Thank you,
Luke, for again, an excellent study in walking
us through so efficiently and succinctly.
And we'll see you all next time when
you tune in for Palm Beach.