Transcript

MIC CAVAZZINI: Welcome to Pomegranate Health, a podcast about the culture of medicine. I’m Mic Cavazzini for the Royal Australasian College of Physicians.

Every now and then a story comes my way that is a great exemplar of how clinical practice emerges from a soup of imperfect evidence, human biases and constraints on the health system. At the RACP Congress in 2024 I encountered one such narrative about the evolving management of pleural disease over the last century.

It was presented by Professor Gary Lee, whose career has spanned China, New Zealand, the UK, and finally Perth, where he established the first dedicated pleural service in the southern hemisphere. Just before Christmas, I chased Professor Lee up so he could share the greatest hits from his more than 330 publications.

Much of the conversation was about pleural effusion, which is diagnosed in about 60,000 people every year in Australia, and is associated with breathlessness and abnormalities in gas exchange and hemodynamics. With mentors in the UK, Professor Lee conducted some of the earliest trials on fibrinolytics and DNAses to break down purulent effusions.
They also put to the test protocols for pleurodesis via talcum insufflation that date back to the 1930s.

Professor Lee’s more recent clinical research has focused on the use of indwelling catheters that a patient can use to drain pleural effusate when feeling breathless. And as we’ll hear at the he has also a made an important contribution to conservative management guidelines for primary spontaneous pneumothorax. This is a long episode, but it’s worth sticking through for the many nuggets of wisdom. 

GARY LEE:            My name is Gary Lee. I'm one of the chest physicians in Western Australia. I work half-time clinical I lead the pleural service in the Charles Gardener Hospital in Perth, and I also work as a Professor of Respiratory Medicine in University of Western Australia. I lead a translational research group in pleural diseases, ranging from multicentre clinical trials to laboratory research in mesothelial cells.

MIC CAVAZZINI:                Thankyou. I’ve also got Dr Marion Leighton to help me out with some practical questions from the generalist’s perspective, particularly in less resourced settings. Kia ora, Marion.

MARION LEIGHTON: Kia ora.

MIC CAVAZZINI:                And Marion is actually one of the “OG” members of the podcast editorial group with us since 2015. Can you tell us where you're dialing in from?

MARION LEIGHTON:       Kia ora, everyone I'm dialing in from Wellington in New Zealand, where I've worked for 25 years. But I also work in rural and regional New Zealand and Australia, and have worked thus in tertiary centres, centres with small respiratory departments and also many centres with no respiratory department. I also work in palliative care and spend some time at the hospice here in Wellington.

MIC CAVAZZINI:                Thank you. So, Gary, let’s start with the pitch you made at Congress and in print in a 2010 article for the Journal of Respirology, about why pleural medicine should be regarded as a subspeciality in its own right. Or rather, why it has been somewhat overlooked in the past. 

 GARY LEE:           Yeah. So, I think when we were medical students back many years ago, pleural disease was regarded as a side issue of many other diseases. At the last count, there's probably about 60 different causes why people can have pleural effusions. So, it often becomes a complication from heart failure, liver failure, renal failure, pneumonia, cancers, et cetera, rheumatoid disease, you name it. And so most specialists viewed it as a bit of an extra from what they are treating the patients for.

And it often becomes a diagnostic challenge, the procedures have over the years become more complicated because there are more options available. And most importantly, we now know that if we do it inappropriately, there's also a lot of safety issues as well. So, back about 20 years ago, when I was still working in the UK as a consultant in Oxford, the UK safety agencies documented that there were unacceptable incidences of pleural procedure mishaps in terms of mortalities, morbidities, et cetera, and that started a whole movement about improving safety of procedures.

First, with the use of ultrasound and then also with training. And then, over the last 10-12, years, we have a lot more research studies guiding us what is the most effective way to get to the treatment and diagnosis of pleural diseases by minimizing the interventions required, both the numbers of interventions and also the invasiveness of the interventions. And all this has contributed to improving patient safety.

And we have exactly the same things happened in Australia, for example, in Western Australia, when I first came back. There was a time when, I think in six months time, there were six patients who died from pleural procedural complications in various hospitals in Western Australia. And then the Health department called for a meeting, and we standardized all the trainings and procedures and things in Western Australia, and we have had a much better improvement in our safety record ever since then.

And since Marion is from Wellington—we trained a lot of rural Fellows, and actually the first pleural fellow we trained, back in 2010, I think, was from Wellington, and that was the result of someone putting a chest train, in Wellington, straight to the heart. And to their credit, they actually published that as a case report in The New Zealand Medical Journal [see also]. And over the last fifteen years, we have trained about 30-odd pleural fellows from all over Australia, New Zealand and also in Asian centres. Many of them have gone back to go and lead their own pleural services and train their own doctors. So, we were able to spread the words around and help to improve the standards around the region.

MIC CAVAZZINI:                And, 2009 was when you first launched that pleural service in Perth. So, where are we at now in terms of resources and training—more formal curriculum, even?

GARY LEE:            Yeah, I think a lot of things have been gradually adopted and incorporated. For example, the respiratory training now in RACP would incorporate mandatory ultrasound training for pleural procedures. And in Western Australia, for example, practically all secondary or tertiary hospitals have a pleural service, and so have most places in New Zealand. We are still a bit behind UK, which is the leader of the movement in the first place, back in 2005 or so. And now almost every secondary, tertiary hospitals in UK would have a nominated pleural lead to be responsible for training and safety standards.

MARION LEIGHTON:       Yeah. I think one of the things that I find difficult with the sub specialisation of areas like this is secondary hospitals in the UK, where I also trained, may have 1000 beds, and it's a very different beast to a secondary Hospital in Australia or New Zealand, which may have 50 beds and might just have one or two physicians, and if you're lucky, you might have one in the specialty that matters at that moment in time, but a lot of the time you won't.

I think there's been both advantages and disadvantages in the need for ultrasound. We now have more and more doctors who can do it, and I think most hospitals have someone who can ultrasound—mostly in ED rather than necessarily within medicine. But do you think we're now at the stage where every doctor should go back and learn to ultrasound, particularly lung ultrasound and maybe some other areas?

GARY LEE:            I think the general principle is that anyone who is going to do pleural procedures probably should have some degree of ultrasound training, even just to make sure that what you're seeing on the chest X-ray is fluid rather than solid. You know, I'm old enough to remember the days that we have something called dry tap. We stick a needle in the patient's chest, we draw no fluid out, and we say, “oh, that's fine, it's a dry tap”. But what you then think about it is that you have stuck a needle in either the lung or the liver or the spleen, and often multiple attempts before you say it's a dry tap. And that is actually absolutely not acceptable. No one in this day and age should have endure this kind of blind darting process to throw a dart at something. I think it does not necessarily need to be a respiratory doctor, it can be ED doctor, as you said, it can be a radiologist, but there should be someone around that can be able to do that, and that's quite important.

MIC CAVAZZINI:                So, let's move on to some of the clinical scenarios you described to the audience at Congress. You said that in Perth, you'll attend a couple of inpatient consults for pleural effusion every day.

GARY LEE:            At least.

MIC CAVAZZINI:                At least. And these referrals come from ICU, post cardiothoracic surgery, of course. As you said, there are over 60 causes, but the most common are malignancies and infection. Now I wasn't totally surprised to read that the incidence and mortality from pleural malignancy has been climbing steadily, but infection? I'll let you put some of the numbers to that. Can you explain what's going on there?

GARY LEE:            Yeah, so pleural infection is actually quite common, and I think that's about 65,000 cases a year in the UK. In the US, the annual cost—inpatient care cost—is about 350, or 400 million US dollars. So, it's quite a significant problem. If you look at the all cause mortality, in Western Australia, about 15 percent of patients who has a diagnosis of pleural infection will be dead within the first 30 days. And depends on whether it's community-acquired, which is about 30 percent or hospital-acquired, which is about 45 percent will no longer be alive in a year's time.

Now, this mortality may not be the best reflection, because we now know that pleural infection is a reflection of the comorbidity of the patients. Patients who are older and frailer and have multiple other medical problems are much more likely to develop pleural infections, and they are the people who might succumb. But when they succumb, it is often to other comorbidities, not necessarily just the pleural infection. So, some of my colleagues in the UK called the prognostic score, the rapid score, which is R, A, P, I, D. Which means that if you got Renal impairment, if your Age is older than 70, if you have Inpatient, which is hospital acquired through infection, and if you got non Purulent fluid, which means that you don't mount an Inflammatory response to generate pus, or your D is to complete the word, so that's Diet, which means that your protein level in the blood is low, which means that you have been ill for quite a while, then you're much more likely to die.

So, the more scores on the rapid score that you have—and it's been proven in large studies—then you're more likely to succumb. But that is actually all cause mortality, which means that you know, if you're old, you're in hospital for another reason, you got kidney failure, you've been ill for a while, so that your protein level is low, then you're more likely to die. So, it's not surprising. So, I think it's important to separate it out that even if we had a magic wand and could cure pleural infection, some of these people might still die. But pleural infection is a marker of frailty. So, one of my good friends, Professor Maskell, in Bristol, likes to call the RAPID score, the CRUMBLING score. And I think that's some truth to that.

MIC CAVAZZINI:                The figure I remember was a 10-fold increase in the last 20 years, but yeah, that might be related to aging populations and other factors like antimicrobial resistance.

GARY LEE:            Yeah, the over 65 is the age group that has the sharpest increase in pleural infection. But we've also had a lot of reports, including in Australia, that children also have increased in pleural infections. And there has been a lot of different hypotheses, and I'm not trying to say that which one is right or wrong. It could be because that we are more hesitant of using antibiotics in some circumstances when they're sick, when they have pneumonia. There is, no doubt, some evidence that the pneumococcal vaccines have significantly reduced the serotypes of pneumococcoids that they covers. But after a small number of years, the number of serotypes that they did not cover then increases, and we're now seeing a lot of pleural infections from those non-covered serotypes. And possibly also because we are now better in diagnosing it and documenting it as well.

MIC CAVAZZINI:                Marion, you had some impression of settings?

MARION LEIGHTON:       Yeah, in rural areas where patients may present later, particularly in northwestern Australia and places like that, I was wondering particularly how urgent both the diagnosis and the potential treatment for pleural infection needs to be. So, should we do an ultrasound and a needle tap on day one, on admission, to know are there bugs there? Or treat for a couple of days and see if things improve before putting a needle in?

GARY LEE:            Yeah. So, that is a difficult balance of the two things in the younger days. Professor Richard Light, who's the founder of Light's criteria of transudates and exudates, used to have a saying that is very quoted, like gospel, to say that, “the sun should never set on a parapneumonic effusion”. i.e. You should not go home until you have sorted the patients with pneumonia and a pleural effusion. And I think that, to some extent, still is true. That we should take it very seriously, that if you don't drain the infected pus—if there's infected pus and you don't drain it, then the patient don't get much better. And in fact, we just had one right on the ward this morning, because of some delay in the management yesterday, because he came in quite late, we didn't have all the initial treatments that we would have in the daytime to start, and then he got quite septic overnight. So, there are cases where there is some urgency to do that.

But I think there's some modifications to, “the sun should never set on a parapneumonic effusion,” these days. In that, if you cover them with adequate antibiotics in the meantime, they should, in most cases, avoid being systemically unwell. You might not be able to treat the pleural component, and so it will still have ongoing infection until you deal with that. But you should, in most cases, with adequate systemic antibiotics, be able to cover the possibility of getting systemically septic or septic shock. So, then it buys you some time.

MARION LEIGHTON:       And do you have a size in mind when you would drain rather than not drain? Because we often see a bit of paraneumonic effusion down at the very lower end of the diaphragm, even just behind the diaphragm, where I potentially would let that resolve on its own, rather than putting in—ultra sounding and putting a needle into it. Would you agree with that? Or would you be keen these days to drain every effusion if it was associated with infection?

GARY LEE:            Yeah. So, again, I think you have to come down to clinical judgment, and also whether you think it is safe to stick a needle and to do the test, or whether it is risky. And that in turn, depends on what is available locally. As you said, in some hospitals, you might not have the local expertise, and you might have a higher threshold of actually testing it or draining it. On the other hand, if the patient is not improving, or you have any concerns. And ultrasound is sometimes quite useful—if it looks like it is an anechoic effusions with no loculations, then you might lean a little bit more towards waiting and watching. If it is looks like a nasty, honeycombing, spider web-type, multilocated effusions, then you might want to intervene earlier.

So, I think it rests on the bedside judgment of what is the best thing to do. As long as we remember the principle that we are treating the infections. We do know nowadays that if you follow the parameters like fever—so what I usually tell my patients is that I will follow them for three things that they need to be getting better. One is they need to look better, including the temperatures and how they look like at the end of the day. Their blood test needs to be better, which is their white cell counts and infection markers like CRP. And the radiology needs to be getting at least no worse. And if all three are going hand in hand towards the right directions, and we're on the winning side, and then you might not need to drain all the locules.

Because nowadays, with CT scans so common, we can see that there will always almost be undrained locules. And I just spent, before I joined this podcast, I was in ICU reassuring them that I think that if the patient is getting better, if there are still some paravertebral or fissural locules that are not drainable, we can just continue with antibiotics and see how it goes.

MIC CAVAZZINI:                Well, let's get into one of the parallel interventions that can help drainage. In 2011 you published results from the MIST-2 clinical trial with Dr Najib Raman as first author. Can you explain for us the role of the tissue plasminogen activator and DNAse in that intervention.

GARY LEE:            So, first of all, I think, I think the work is mainly from Naj Raman and Rob Davis. I was fortunate to be part of the co-authors in the New England Journal. But we did play a strong role in introducing it into Australasia, and we certainly have done a lot of papers and research studies on this topic since then.

So, pleural pus is difficult—or pleural effusions are difficult to drain, mainly because often they are loculated in pockets, and also they might sometimes be thick, such as in pus. So, the initial first trial that Professor Davis has done with Nick Maskell in the New England Journal was actually to test whether fibrinolytics works. And that was actually a very important study, because it actually shows that fibrinolytics did nothing at all on the first randomized trial on 400 and something patients, disproving conventional thinking that fibrinolytics actually do any good.

And it's only in the second trial, when it was combined with deoxyribonuclease or DNAse—or Pulmozyne is it’s trade name— that in actually putting the two together has a synergistic effect and actually improve the drainage such that about 90 something percent of the patients in the trial were treated successfully without having to require surgery.

So, Pulmozyne is something that we have been using for cystic fibrosis patients to thin their sputum for many, many years. But fibrinolytics by itself, or the deoxyribonuclease by itself, neither of them provides any improvement over placebo. So, this was an interesting kind of phenomenon, and led us to the hypothesis that this is the fibrinolytic that break the loculations and the deoxyribonuclease that thins the pus.

So, we don't 100 percent know all the mechanisms, but it does show that in centres like ours, very few patients will actually have to go through surgery for clearing pleural infections. In fact, so much so that a lot of times our cardiothoracic surgical Trainees fail their training quota in our Centre for doing pleural infection, video-assisted thoracoscopic surgery.  

MARION LEIGHTON:       On that note, again, with timing, I was really impressed, actually, when I read the studies as to how much better the two together were, and I was thinking, if you’d ultrasound it and it looked loculated or honeycombed, is it best just to get in and give both straight away, rather than waiting a day or two and seeing how much comes out of the drain, which I feel is more our current practice in smaller centres.

GARY LEE:            Yeah, I think, if you put a tube in and the fluid doesn't come out in the next small number of hours, it's not going to come out. So, you could wait a day, two days, three days, and you know, it's not going to suddenly improve. So Back in 2005, I think, when, when we first started using it in Western Australia, that was very new, and we seemed to be a bit more conservative. But nowadays we have a lot of confidence about its safety, and so we tend to use it much earlier.

And one of our friends in New York is starting a study of using it within a couple of hours, so that they just put in the drain aspirate as much as they can, and if there's nothing coming out after that, to start it right there and then. We tend to, more likely, to put in a drain throughout the day. So, very often, it would be in the in the mid afternoon or late afternoon. And we won't even have the biochemistry back for another hour too. And I'll be a little bit hesitant of starting fibrinolytics in the late evenings and things in the after hours. So, we'll probably most likely doing it first thing the next morning.

MARION LEIGHTON:       Why would you be reluctant to do it out of hours? What are the side effects or potential complications?

GARY LEE:            Yeah, I think, first of all, I like to see all the initial biochemistry of the fluid and things to come back to make sure that we are on the right track. And secondly, in most cases, it is quite straightforward. In about 1/3 of the patients, they did require escalation of analgaesics. Pain seems to be happening most likely in the first dose, and no matter how bad the pain is, it almost never happens on second dose. I've done many, many hundreds of these, and I think there's only one or two cases where people still have pain after the first dose.

Now why is there that pain? Again, many hypotheses, it might be related to breaking of the adhesions, which is the most popular hypothesis, but again, it's not proven. But in our experience, we often warn the patient that they might be a chance of having pain in the first dose. But since we have also been embarking on the dose de-escalation series, we're using lower doses, and we're seeing far less common of these complications.

They are uncommon complications, but because we do it so often, we do see them at least a couple of times a year where the patient might actually have an underlying bronchopleural fistula. So, you actually have a connection from the lung opening up into the visceral pleura to the pleural space. So, when you then actually inject the tPN DNAs into the pleural space, it actually goes backward and it gets coughed up, so the patient will cough up the fibrinolytics immediately. And, you know, it does not cause any harm. You just have to stop using it.

MIC CAVAZZINI:                So that that first very small trial was followed in 2014 by an off-label trial with 107 participants, who were—they were still septic after treatment with intrapleural antibiotics. And here, as you mentioned, 100 out of 107 patients treated with tPA and DNase were successfully managed without the need for surgery. Fluid drainage before enzyme therapy was just 250mL, whereas in the 72 hours following treatment it was 2 and half litres of pus. But there was a bit of an academic bun fight about these findings in the journal, Chest. These other groups in Washington DC and Omaha that believe that DNAse provides no benefit on top of tissue plasminogen activator. Have I understood that debate correctly?

GARY LEE:            Yes. So, the question is, if you give enough fibrinolytics, like much bigger doses, whether, whether you can overcome and does not need the deoxyribonuclease. Like most things in in pleural disease, the doses initially used for these kind of treatments were empirical. It does not come through a dose escalation study, those finding series, et cetera, and it was just what some case reports is reported. So, that remains a question of whether, if you use more fibrinolytics, then maybe you don't actually need to have a second agent.

However, the fibrinolytics do have some degree of bleeding risk. At the moment, using the doses of, say, 10 milligram, most series show less than 5 percent bleeding risk. And the bleeding, if it occurs, is a diffuse venous ooze. It just means that it drops your haemoglobin gradually, is not an arterial bleed, something like a GI bleed, where it drops your blood pressure and becomes hemodynamically compromised.

So, do remember that a lot of these patients, as I said, have got multiple comorbidities. They might start from a low haemoglobin, then you might have to top them up with some blood, and then you just stop the fibrinolytics, so it doesn't usually come to any harm or life-threatening bleeding. But nonetheless, rather than escalating or doubling the dose of fibrinolytics as some other groups have tried, I think we are very happy with using the two agents at the moment,

MARION LEIGHTON:       I found it's very easy to get tPA in the very small hospitals because we use it for other purposes, but the DNAs has been harder to come by, if particularly we you know, thinking about those after hours periods that worry us all,  four day Christmas, public holidays and Easter, is this a sort of time when it's worth actually sending someone down to a larger centre to get both in sooner, rather than trying to manage it with a higher dose of fibrinolytic. Or sitting and waiting for five or six days in a smaller centre.

GARY LEE:            Yeah. And I think, you know, a lot of other places I have been involved in would just keep a small amount of DNAse. They're not particularly expensive, they've got a reasonable shelf life in the fridge, and as soon as they're used for one patient, they replace it. That kind of other strategy can be used as well.

But you raise a very, very important question. A lot of times, we don't think about how difficult implementation of something is. So, we find this treatment is proven in New England Journal, is confirmed in open label studies, and it has a dramatic effect on patients. But when we actually try to promote it around the world-DNAse is used mainly for patients with cystic fibrosis. So, in our Asian neighbors, for example, where cystic fibrosis does not exist, the drug is not licensed. And to license it only for the purpose of pleural infections is not economical. So, it was actually very difficult in the first many years to try to have Asian countries using this regime.

And again, it just requires one or two enthusiastic individuals to find a way. In Hong Kong, I think one of the smaller hospitals actually started it. When the larger hospitals said, “It is difficult. We can't get it. It's not licensed”. But the small hospital, without surgical backup, managed to have out-of-label approval to use it on a case-by-case basis, and they used it. They were so successful, they showed the cases around Hong Kong, and then everyone else is now using it.

Similar things happen in Singapore. In Malaysia, one of our trained Fellows goes back there and finds that the rules are a bit easier to navigate in university hospitals than in government hospitals. So, these kind of things are local logistic and implementation problems that you don't often think about how difficult it is. And also, another interesting point; the tPA [dose] for stroke and for heart attack is for 100 milligrams. So, for example, in Hong Kong, the company only ships in 100 milligram ampules. So, when you're using it only for 10 milligram, or in our latest dose de-escalation series, we're using 1 milligram, we thought that we would save a lot of money, saves a lot of fibrinolytics for people. But in those places, each ampule is 100 milligrams, so it's very, very expensive. And the shelf life once opened is 24 hours. Whereas in a lot of American hospitals, they have 2 milligram ampoules, and they adopted outdoors de-escalation immediately. So, these kind of interesting things is just that you never think about until you actually put it into the bedside and find all these hurdles.

MIC CAVAZZINI: After infection, the next major cause of pleural effusion is malignancy. Almost all patients with mesothelioma will experience pleural effusion. But many other cancers also metastasise to the pleura and cause these symptoms. Around a third of all patients diagnosed with breast cancer and a quarter of patients diagnosed with lung cancer develop pleural metastases. As Professor Lee put it in his presentation, cancer cells can walk around from the lung to the parietal pleura or swim across the fluid filled space.

While curative options for people with pleural malignancy are limited, there are tools for control of pleural effusion. If surgical drainage isn’t enough, pleurodesis limits the swelling and breathlessness.

Mechanical pleurodesis is where the lining of the chest wall is surgically roughed up or lifted to allow the lung to stick to it. In older patients and those with cancer, it’s more common to spray a coat of sterile talcum powder to the chest wall. This causes inflammation and then results in adhesion of the lung.

The use of talc has an interesting back story, and was first described in the published literature in a 1935 case series in the Journal of Thoracic Surgery. After trying out the technique on cats and dogs the experimenters moved onto patients, and refined their delivery method with a specialised blower.

This is how the outcomes of the intervention in a 14 year old girl are described, after receiving  “One-half dram of one half per cent iodized talc, powdered over the upper and mid lobes under thoracoscopic vision. Upper and mid lobes firmly stuck to the chest wall.” And then, “Ten months have passed since the first clinical case was operated on, and up to the present there is no reason to believe that ill effects are to be expected from the presence of this insoluble powder between the two pleural surfaces.”

Talc was licenced as a medical device, rather than a medicine, but this was well before more rigorous safety testing and regulation became a thing. So, use of the technique just carried on for decades without question. It was only in 1997 that the Lancet published concerns from some Brazilian physicians about the adverse outcomes from talc insufflation. From 255 patients they observed four who developed bilateral pulmonary infiltrates, hypoxaemia, hypercapnia, mental confusion and hypotension within two days of the intervention. All four patients required intubation and mechanical ventilation and three of them died with the diagnosis of acute respiratory distress syndrome.

It was around this time that Professor Lee came around to examining the problem during a Fellowship at the Oxford Pleural Disease Clinic, at the Churchill Hospital.

GARY LEE:            So, I did my PhD with Professor Light, and Professor Light always said, “Talc is dirt from the ground, and we're putting dirt in the ground in people's chests.” Which is to some extent true.

So, talc has a very special biochemical formula which I can't quite remember—it’s very long with many elements. And when a lot of countries actually go and look into their products they're using many of the places were not using talc, they were just using white powders of other chemical descriptions, biochemically or physically very, very different.

So, it's actually Professor Rob Davis in Oxford who took a strong interest. Professor Light also took a strong interest, and together, they started doing studies in animals and also in humans. And one of the landmark studies that Nick Maskell and Rob Davis did, which I was the coauthor, was to actually compare the talc with other agents of pleurodesis, like doxycycline, and shows that people who have talc did have more hypoxemia and lung inflammation. And then they go and compare talc particles of different size and randomized the patients and  find that those people who have small particle size in the talc preparation have got significantly more acute lung inflammation, more hypoxemia afterwards. And the actual mechanism is still unclear, but it is presumed that the small particles get absorbed through the lymphatics, go into the blood and go and get lodged in the lung and causes lung inflammation.

So, since then, that has actually changed the world. At one stage, the UK authorities issued a letter to banned all the talc preparations and had to relicense them, and only the ones with larger particle size are licensed in the in the UK. And in one of the large—400 something patients malignant pleural effusion studies done in the US—actually quite a significant percentage of patients did have acute lung injury. So, by doing this licensing processes and ridding out the more harmful preparations, it has actually saved millions of people's lives.

MIC CAVAZZINI:                And you’re leading an international collaboration to find alternative interventions to talc. The program is called AMPLE, for Australasian Malignant Pleural Effusion, but actually has sites in Canada, the US, the UK, Hong Kong, Singapore and Malaysia. The first RCT findings were published in 2017 in JAMA and this was a comparison of talc pleurodesis to installing an indwelling pleural catheter that is under the patient’s control. Can you explain a bit more?

GARY LEE:            So, as I tell most of my patients, I'm just a glorified plumber. I'm not there to cure the cancer, but we're trying to drain the effusion so that they can breathe better, which is important for most of these patients with advanced cancer, much shorter breath, and it affects their quality of life and things that they can do in the day.

If we think that the conventional way of putting the patient in hospital for quite a few days, putting the tubing, putting the talcum powder in, and probably about 1/3 of the patients, their lung does not expand and they never get pleurodesis. For the ones that actually have the lung expanded, the talc success rate is about 70 percent, so, all in all, only half of those patients will benefit from the talc pleurodesis. So, maybe the more simple way is just to drain the fluid, because that's all we wanted to do.

So, the indwelling pleural character is a 15.5 or 16 French gauge plastic tube, silicon made, and so it is about six millimetres in diameter and is put into the pleural space tunnel underneath the skin, then it comes out with a small plastic one way valve, and the patient can then go home and, if-and-when needed, connect to drainage bottles when their fluid builds up. So, that saves them from coming to hospital, and it saves the number of days they spent in hospital.

So, if you actually look at the number of days patients in hospital for whatever reason, when they were treated with the conventional talc pleurodesis, they spent about 11 percent of their remaining night in hospital. But those who were randomized to have indwelling pleural catheters spent and about 6 percent of their remaining life—days in hospital. So, it is priceless to a lot of these patients. But more importantly, those who have talc pleurodesis, about 25 or so percent have to have further needles or tubes put in the chest. But less than 5 percent who have fitted indwelling pleural catheter have that.

MIC CAVAZZINI:                I think I read that the indwelling catheter reduced by two days in median, the time each patient would have spent. And across Australia, you estimated that would be 14,000 bed days a year. That practice has been adopted as first line in the US and the UK for management of these patients with malignancy. What about Australia? Where is the standard?

GARY LEE:            I think at the moment, we have many different options now, and the indwelling pleural catheter is now accepted as one of the first line options, together with surgical pleurodesis, thoracoscopic pleurodesis by medical thoracoscopy, bedside pleurodesis might still have a role in some of the patients. So, I think it is certainly up there as one of the options, and it depends on the local expertise, the local preference.

And a lot of times, we now advocate that it should be the patient preference that should count in these kind of settings, because each of these modalities has got pluses and minuses. They are patients who would want to avoid having spend any time in hospital and want to be out of hospital as much as can. That was particularly a major issues during COVID times that everybody wanted to avoid being in hospital. So, indwelling pleural catheter would be a very good thing. There are, however, also other people who think that having an implanted device in the chest is not what they want. It certainly comes with a bit of need for aftercare, and there's more risk of infections and blockage and leakage, et cetera. So, if that's what not what they wanted, then there might be other options that might be more suitable.

MARION LEIGHTON:       I remember Dr Nicholas Smith coming back to Wellington and 2010 and setting up our service and starting doing indwelling catheters. And we were all very excited. And I'd say, I've seen them work extremely well. However, yet again, when I'm in places much more rural, we don't have people who can put them in. And it's not so much patients not wanting devices in their chest, but people don't want to travel. They don't want to go to the big centre a number of hours flying away in their last weeks of life. Have we come far enough in the last 15 years that this is something that, potentially, someone local could put in, rather than it being something they have to come to a subspecialty service for? I mean, we've managed to get to the stage where we can put in renal dialysis catheters in most places.

GARY LEE:            I think the insertion, you just need to train someone up. It is much more the aftercare and needing to troubleshoot that is the main difficulty. I mean, in Western Australia, we cover very vast land mass, and we do have a reasonably good service nowadays, with telehealth, et cetera, to try to troubleshoot. And a lot of times we do train the patients’ carer to actually do all the drainages. And they can ring us, they can Zoom us and show what is the problem and we try not to have to bring them to Perth a lot of the time. But yes, I mean, that would often be one of those factors that may dictate whether you want to try other modalities rather than an indwelling pleural catheter for the rural patients and use it as a second or third choice in some of those cases, yes.

MIC CAVAZZINI:                And you’re almost coming to the end of the AMPLE-3 comparing these indwelling catheters to mechanical pleurodesis, which has conventionally been said to be the gold standard. What have you found there, or is it too early to spill the beans?

GARY LEE:            We haven't got the answers yet, but that was a difficult trial. It is a very important trial. It is NHMRC funded, and everybody in the world is looking forward to seeing the results, but the opinion is very polarized. We've done surveys in Australia and New Zealand, for the people who had advanced cancer with malignant pleural effusions, for the people who had trapped lungs, everyone agrees indwelling pleural catheter is the best thing. For the people who have longer, better prognosis and the lung expand, the surgical community overwhelmingly thinks that surgery is the right thing and the only option.

The respiratory doctors were split three ways quite evenly, of bedside pleurodesis in the hospital, indwelling pleural catheter or surgery. And I think you'll find that in for example, in North America, in Sydney and in Melbourne, there will be a lot more people who are favouring surgery. In Western Australia, or maybe New Zealand, there'll be more people favouring IPC, and so it is in the UK. So, the world is very, very split about that. And for that reason, like in a lot of other trials we have done, this is the most important time to actually do a randomized trial, because other series are just all full of selection bias. And you know, you think that this person will be good for surgery, so you do them, so all the surgical series looks very good, and so on.

But when you do a randomized trial in a very polarized situation, it was a very difficult trial to recruit, and that's why it took us quite a few number of years. But we persevered, together with the help of all the other multiple centres, and we got our 148 patients a few months ago. But we are having a 12 month follow up period, so I don't have an answer to tell you at this point.

MIC CAVAZZINI:                So, in the final ten minutes, let’s go to another common and baffling presentation within pleural disease and that’s primary spontaneous pneumothorax. You showed scans from a patient with a completely collapsed left lung and said that in med school you would have been taught that the person needed urgent drainage. And most literature on primary spontaneous pneumothorax management focus on the size of the drainage. Small bore vs large bore drains or needle aspiration. But again, this was an example were underlying assumptions had gone unchallenged for a long time. Does it need intervention at all or can it be managed conservatively. So, tell us about the PSP trial published in the NEJM a couple of years ago.

GARY LEE:            Sure. Pneumothorax is a hole in the lung, or holes in the lung. Air leaks out, and then it gets trapped within the chest wall, and so the lung gets more deflated and patients get more breathless. And if we put a tube in, it makes the X-ray looks better, and it does make all the doctors feels like that they're doing the right thing. But back in the 1960s there was actually a lot of papers to say, is this the right thing to do? Does pneumpthorax to be drained, and the most famous one was by Peter Stradling, who is a consultant in Hammersmith. And his son, Professor John Stratling, is a very famous chest physician in Oxford, and we had the chance of working with John. And when I was working with John, and he would always say, “Why do you pleural people like to drain pneumothorax. You should just let it stay down”.

And the theory is that if you have a hole in a balloon and you want the hole to heal, then if you let the balloon stay down, the edges of that hole will come closest to each other, and then it theoretically might have a better chance of closing up and closing up better.

MIC CAVAZZINI:                If you deflate the balloon?

GARY LEE:            Yeah, if you allow the balloon to continue to stay down deflated. Whereas if you put a chest drain in, you expand the lung, and you are actually pulling the edges of the hole further apart, and God forbid, we put suction on the patient and the constant bubbling of air through the through that hole, it's a miracle that any of those holes actually heal.

So, that is the hypothesis behind it, but that is 180 degrees opposite to what we were trained to do. And so again, that was a very controversial trial, but thanks to the trial groups throughout Australia and New Zealand, there's a joint effort for the, I think it's 39 or 40 emergency department and also respiratory departments joining hands. They got the 340-something patients randomized to the two arms. Again, it was very controversial, very polarized, some people say, “this is this is totally not right, and you cannot allow the patient to have that chest X-ray and go home. That's just not acceptable, they cannot be in the trial”.

So, there were a lot of difficulties recruiting, but again, because it is such an extreme difference in practice, it is the important topic for doing a randomized trial. And the trial shows that if you look at the patient in eight weeks time, there was actually no difference in the X-ray. But if you do put in the chest strain as according to the hypothesis, they're much more likely to have persistent air leak. They take much longer to heal. Many of them will require surgery. So, I think it is five times more likely they have persistent air leak, four times more likely that they required surgery, and three times more likely that they will have complications. And interestingly, two times more likely to have recurrence of the pneumothorax within 12 months.

So, that was quite overwhelmingly convincing for a lot of people. But again, just like anything to try to change practice, especially 180 degrees from what you have been taught, does take time. So, we find that in Australia and New Zealand, because the trials were actually done here, we had a much better uptake at the moment. But when I go and do talks in United States, for example, other places in Asia, there it is an entirely new concept, and it's taking time for people to come to accept it. But I think the most likely thing is that people always has allowed very small pneumothorax not to be drained, and over time, with all this evidence, people are going to let bigger and bigger pneumothorax not to be drained, and they will build up confidence, and it will become the standard.

MARION LEIGHTON:       As generalists, we were very excited with this study, because we love doing less, rather than more if we can. We don't gain anything from procedures. But one of my questions was, yeah, is there a, “it's too big? It needs a drain.” Obviously, if there's any sign of a tamponade, but would you have any other clinical criteria that would make you think maybe we should drain this? If the patient's particularly hypoxic, their respiratory rates up, rather than just subjective breathlessness? Or would you maybe give it let's sit on it overnight and see how things are in the morning?

GARY LEE:            So first of all, I need to put in the caveat that this is the trial for primary, spontaneous pneumothorax. Not secondary, not traumatic, not iatrogenic. The importance of that is because if your’re a primary, spontaneous pneumothorax, you got a healthy the lung, so you should not actually be too breathless. So, I always encourage people to think, it doesn't matter how large the pneumothorax on one side is, because if you think about this healthy young man, if he has a total pneumonectomy for whatever reason, he can still go around, go to work, go to school with one lung, and he'll be fine, and he won't come into any problems.

There is a set of strict safety criteria in the New England Journal that they cannot be too hypoxic, tachypneic or tachycardic et cetera. But if you actually look at the patients carefully and talk to the patients carefully, breathlessness is a feature, but is not usually the main feature why they come to hospital. It is always pain. And I would even put that number two is actually anxiety. They don't know what is happening, they don't feel well, they have pain, they think they're having heart attack or dissection of the aorta, and they think that they're going to die. So, they rush to hospital. But if you talk to them, once you settled them with painkillers, once you settled them by explaining what is happening and they're not going to die from this, this is a nuisance rather than a life-threatening event, then they calm down.

And then one of the most important rule out of the safety criteria in the New England Journal trial is that if the patient can walk with us for two rounds around the emergency department, then you'll be fine. Obviously, some emergency department are bigger than the others, but we find that rule is actually very, very good. If you can actually walk around and they're well, it should be fine. The cases where they actually couldn't, some of them, even though the X-ray looks normal when you CT scan them, they have actually underlying lung disease. So, that rule is actually even more important to me than a lot of the physiological parameters.

MIC CAVAZZINI:                That's quite interesting. That example you just gave the walk around the ED—so in the UpToDate guidelines that you contributed to, it suggests that management of primary, spontaneous pneumothorax should be guided by symptoms, not the size of the pneumothorax on X-ray. So, you know, you've described symptoms reported by the patient, like pain or this walk around the ED. Is it hard to give up what feels like in a more objective measure in the X-ray? Does that feel more concrete?

GARY LEE:            I think we'll do all of them and I often actually tell the patient, are you feeling okay to walk? And then I just walk them while I take history. And then if they keep pace with me and talk to me in full sentences all along, I think they will be fine. We do have a safety criteria that the patients do have to have a serial X-ray in a few hours time just to make sure it hasn't suddenly changed. But otherwise, after that, we have left a lot of people with complete pneumothorax, and we have published a small series of those subsets of patient with complete pneumothorax, almost 50 of them in a trial, and they did the same successfully with conservative management.

In fact, if your lung is completely down, there's actually no more air that can escape. There's no more air, that it will actually get worse. The other question, a lot of times, that comes up is people say this patient has got mediastinal shift on the X-ray, so we have to put the drain in. “Tension pneumothorax”, the correct definition is actually pneumothorax with hemodynamic compromise, so we're trying to tell our radiologists that unless they come and check the blood pressure and the pulse rate of the patient they should not use the word tension pneumothorax. They should use the word “mediastinal shift” on the X-ray report, because once they use the word tension then people who seeing the patients get panicked, and then they will put in chest strain. But statistically, only about one in 10 patients with mediastinal shift actually have hemodynamic compromise, and they're usually not the primary spontaneous pneumothorax patients. They're secondary spontaneous patients.

MIC CAVAZZINI:                Those human factors of practice are the most interesting stories for this podcast. And finally, yeah, it's still a hot topic. And, finally, in February last year there was a case report published in the New England Journal accompanied by two essays, one advocating for your conservative management approach, and one arguing for insertion of a chest tube. And two thirds of the more than 2000 readers who voted on this were compelled by the first, conservative approach. So yeah, is that—

GARY LEE:            Yeah. So, that was a, I think it's the New England Journal, Evidence Journal, which is a subsidiary nowadays. And they make up scenarios and then they asked for pro-con sections. And Professor David Feller-Kopman who argues against the conservative management, wants me to tell the world that he's actually very much for conservative but he's been asked by New England Journal to write the con, so that's why he's doing it.

MIC CAVAZZINI:                It’s like a debate. You’re sent up to debate, regardless whether you agree or not. But it's fascinating that most of what we've discussed today has not been so much about new knowledge, or whizz-bang interventions, but challenging old dogma. And maybe we can learn by looking at the world around us, as well. Do you want to finish with the story of the elephant?

GARY LEE:            So, animals actually have very different pleural structures, and if you look at different animal species, we actually learned quite a lot of interesting things. The elephant, for example, is actually born pleurodesed, so they have no patent pleural space. So, never go and stick a needle and try to drain a pneumothorax or pleural effusions….

MIC CAVAZZINI:                Any vets listening.

GARY LEE:            And this is based on the small numbers of post-mortem dissections on elephants, especially in the, I think, the Boston and the Melbourne zoos. But there are a lot of other interesting things, like, for example, the American buffaloes, they actually do not have a complete mediastinum, so if you cause the pneumothorax on one side, it will go and compress the lung on the other side. And it is believed that the indigenous people kills these buffalo by basic arrows and bows by shooting in between the ribs cause the pneumothorax, and causes tension pneumothorax, and the buffalo is killed.

But even in in small animals, for example, mice do not have a complete mediastinum and hamsters don't, and so on and so forth. Cats and dogs, apparently has more chylothorax and so on. So, there's a lot of interesting pleural variations.

MIC CAVAZZINI: Many thanks to Professor Gary Lee for taking us on this fascinating journey. I’ll provide links in the show notes to The Pleural Medicine Unit he directs and the Institute for Respiratory Health in Perth. I also want to thank Dr Marion Leighton, not just for being such a great co-host on this episode but for sticking around for so many years to review and improve the Pomegranate Health podcasts.

There were several other physicians who kindly listened to early drafts of this story and they’re all thanked by name at the web page racp.edu.au/podcast. Another one of these reviewers wanted me to give a plug to the National Lung Cancer Screening Program, due to launch in July of this year. It will fund use of low-dose computed tomography (LDCT) to screen for lung cancer in high-risk Australians with no signs or symptoms. Risk is determined by a history of at least 30 pack-years of cigarette smoking and either still smoking or having quit in the last ten. For more information, go to the health.gov.au website.

This podcast was produced on the lands of the Gadigal clans of the Yura nation. I’m Mic Cavazzini. Bye for now.