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.