Recorded at the 6th McMaster International Review Course in Internal Medicine.
All lectures available at the MIRCIM virtual platform, click here to buy access.
Professor Paul O’Byrne: Hello everybody, and a very warm welcome to you all. Thank you for joining this question and answer session that [will] be discussing the presentations of 4 outstanding colleagues and presenters, who have discussed a number of important topics in respiratory medicine. My name is Paul O’Byrne; I’m a professor of medicine [and] dean of the Faculty of Health Sciences at McMaster University in Hamilton, Ontario. I’m a respiratory physician by training. So I’ve had a chance to attend each of the presentations and I know there will be a lot of vigorous discussion and debate as a result of these excellent presentations. I want to begin firstly by thanking the organizers and the committee that helped pull together the MIRCIM 2021 meeting. This is the 6th McMaster International Review Course in Internal Medicine. Normally we get together in the utmost gorgeous city – in Krakow, Poland – but this year because of the limitations imposed on all of us, this is an entirely virtual meeting. I want to firstly welcome the 4 presenters, and I will briefly introduce them. And then we will have some questions that have already been sent in by the people who have had the chance to view the presentations. But also to remind you – there is a chance to ask questions [and] engage in debate during the session itself. So there is a question and answer function on Zoom and it’s possible to put a question in there. And we will do our very best to get to as many of these as possible. So, I will begin, then, by introducing our 4 panelists, beginning with Professor Wisia Wedzicha, who is a professor of respiratory medicine at the National Heart and Lung Institute at Imperial College in London. Professor Wedzicha is a world-renowned expert in the investigation and management of COPD and is also currently the senior editor of the Blue Journal, the main respiratory journal that we have, American Journal of Respiratory and Critical Care Medicine. Professor John Kolbe is a professor of medicine and head of the Department of Medicine, the Faculty of Medicine and Health Sciences at University of Auckland, also a respiratory physician. He has previously been the president of the Thoracic Society of Australia and New Zealand, but he is currently the president-elect of the International Society of Internal Medicine. Professor Najib Rahman is a professor of respiratory medicine at the University of Oxford, currently the Director of the Oxford Respiratory Trials Unit. And Professor Rahman is a world authority on pleural effusions and their management. He will be addressing the questions on his presentation around pleural effusions. And finally, a colleague from McMaster University, Associate Professor Bram Rochwerg, who is an intensivist and member of the Department of Medicine and who has immense expertise in the development of network meta-analyses [and] randomized clinical trials and has been a very important lead in many of the practice guidelines methodology around critical care and the management of acutely ill patients. So thank you all, again, for joining, welcome. And I’m going to begin by addressing the first question we have received to Wisia. And the question is, “The GOLD report on COPD for many years has underlined that integrated care is not a standard in the management of COPD because of a lack of evidence. Could you just comment on why there is still little evidence in integrated care? What could be done to correct this?"
Professor Jadwiga Wedzicha: That’s a very interesting question and I think, first of all, I will defend the GOLD committee by saying this is something that’s being gradually developed. I think that is very important. We’re learning more about integrated care. I think the problem is that studies are very difficult to carry out. There have been a number of studies on integrated care that haven’t probably given the results that one would want. For instance, the outcome may be a reduction of exacerbations, and you find suddenly when there is integrated care patients have more exacerbations; they are more likely to report them. That’s just one of the difficulties. I think integrated care is very important for COPD because COPD is a heterogeneous disorder with many phenotypes, so we need a multi-disciplinary approach. I think this is something that GOLD is taking onboard. If you look at the recent report, there is even a whole chapter of multimorbidity. So that shows that we’re going in that direction.
Paul O’Byrne: Thanks, Wisia. The next question I will address both to actually John and Wisia because it relates to bronchiectasis in patients with COPD. And the question is, “Should we consider chronic macrolide use in all patients who have COPD but associated bronchiectasis?” Maybe John, I will ask you first and then we’ll have the comments from Wisia.
Professor John Kolbe: Thanks very much, Paul. And I am sure this question is based on a fact that there are a number of studies showing that a substantial proportion of patients with COPD do in fact have bronchiectasis – approximately 50%. In my talk I emphasized the fact that bronchiectasis is in fact a clinical syndrome and not simply a radiologic finding. Many patients who have COPD, the radiologic evidence of bronchiectasis is thin-wall, cylindrical bronchiectasis involving the basal segments of the lower lobes. And those patients may or may not have the clinical features of bronchopulmonary suppuration with a lot of cough and a lot of sputum. So the first thing I would say is, “Does this patient actually have bronchiectasis – that is, the clinical syndrome – rather than a radiologic abnormality? Remember that the radiologic diagnosis of bronchiectasis is an increased bronchial-to-arterial ratio. Now, that can be increased because the airways, the bronchi are dilated, as in typical bronchiectasis. You can also have an increased ratio because the arterial branches are in fact smaller than usual. And there is some intriguing evidence to suggest that in some of those patients with chronic airways disease, there is some degree of vascular narrowing, possibly due to local hypoxic vasoconstriction. So I guess the first thing is [whether] the patient actually fit[s] the clinical syndrome of bronchiectasis. Moving now onto the question specifically, and that is the use of macrolides. As I pointed out in my talk, there are three very large, good-quality randomized controlled trials that show benefit for macrolide therapy in bronchiectasis. However, those studies that have looked at it have demonstrated the development of macrolide resistance. The clinical significance of that is not entirely clear, but I do not think that even [all] patients with bronchiectasis should necessarily be on macrolide therapy. And there is little evidence to suggest exactly who should be receiving macrolide therapy, but most guidelines have suggested that it’s those with higher morbidity. So it’s those who are having a lot of symptoms of bronchopulmonary suppuration with a lot of cough and a lot of sputum, or those who are having frequent exacerbations.
Paul O’Byrne: Thank you, John. Wisia, anything to add?
Jadwiga Wedzicha: Yes. Well, I think GOLD has actually pronounced on this. And again, GOLD suggests [that] after optimal bronchodilation, if you have bronchiectasis or low eosinophil count, they recommend macrolides. I use macrolides all the season. Again, most exacerbations in the only UK occur between autumn – September; it’s in reverse, of course in New Zealand, September to May. And I treat patients usually end of September to the beginning of May with a macrolide and give then rest over the summer. John, whether that does anything to macrolide resistance is another matter. But there are few exacerbations, in fact, very few exacerbations in the summer months. So my answer is: yes, this is the group I would favor for macrolide therapy, but I’ll use it for 8 months a year.
Paul O’Byrne: Could I follow up, John, just by asking your sort of best guess? I’m not sure there is much concrete evidence either way here, but is the effect of macrolide on the microbiome in the airway? Or is it some other effect? Or do you think it’s a combination of effects? And I’m asking this because of the evidence that macrolides can in some patients with severe asthma provide benefit in exacerbation risk reduction; although the evidence is not hugely convincing, there is enough to at least warrant consideration of it. And there, the microbiome may not be quite as relevant as in bronchiectasis.
John Kolbe: The short answer, Paul, is “I don’t know.” The longer answer is that macrolides seem to have a multiplicity of effects. It would seem that the harder you look, the more effects of macrolides that you find. I mean, if I go back a huge number of years when I was involved in a laboratory-based studies, we used macrolides to influence the function of the alveolar macrophages, even in those very early years. So it’s likely to affect innate immunity, it’s likely to affect the individual members of the respiratory biome. Goodness only knows what is does to the interactions that occur within that respiratory microbiome. So I don’t know, Paul, but I would be surprised if it wasn’t a multiplicity of effects, both on the organisms and on immune system.
Paul O’Byrne: Great, thank you. I have a question, Najib, around your presentation on pleural effusions and their management, which by the way, if you haven’t attended it, it was just outstanding: very evidence-based and very, very useful. The question was, “What’s your opinion on measuring pleural pressures during thoracentesis?”
Professor Najib Rahman: So thanks, Paul, that’s a great question. Thanks for having me on this great panel. So, we would all love to measure pleural pressure because it’s kind of physiology, we’re respiratory physicians, we love to see the curves, it’s all great fun. The problem with that statement is does no good to the patient or to you. That’s my summary of where we are with the debate on pleural manometry, and I will just summarize that very quickly. It was assumed early on that measuring pleural manometry would allow us to predict important side effects for the patients, [such as] trapped lung, major issues like re-expansion pulmonary edema. And we know from good, evidence-based, large observational studies that it absolutely doesn’t predict the recurrent severe re-expansion pulmonary edema. So that’s a Yeti. It happens when it happens and we can’t recognize it. So it doesn’t do that. There has now been a randomized trial that was published in [00:13:44] Respiratory [] last year, but a lot of it was driven mainly by the guys in Vanderbilt. They did a beautiful study, looking at the patient-focused outcome measure. And this was [] thoracentesis by a 100 mL []. And they demonstrated convincingly that using a simple approach to thoracentesis was every bit as good as using manometry in preventing pain-related thoracentesis. The one outcome, Paul, that was different was the number of people who had pneumothorax ex vacuo. And I think that’s important. Pneumothorax ex vacuo, just for the audience, simply means that air has been entrained because of a negative-pressure pleural space, but it doesn’t really have a clinical implication, that. You recognize it on a chest X-ray. I guess if you pushed very hard and said, “the patient’s about to fly to Canada, you may want to know” – I guess that’s true but other than that, I don’t think we should be using manometry. My final point on this is there may be a future is a pleural manometry, which is predicting what we call the pleural elastance. That’s pretty much a measure of how much the visceral pleura wants to [00:14:54 – problem with connection] the parietal pleura. And that may, it may help to predict who will have a good response to pleurodesis.
Paul O’Byrne: Thank you very much – a very comprehensive answer. Thank you, Najib. Could I also follow on a question of my own? Because this crossed my mind as I was watching your presentation – and that was something close to my heart and I felt very positively about it, that was the indication or the suggestion that we should still rely a great deal on thoughtful clinical processes, particularly in relation to left ventricular failure, before putting needles into people with effusions. And I’m just wondering, because of the temptation of having a portable ultrasound machine at everybody’s right hand or left hand – depending which hand they use – to put a needle in. How do you try to avoid that temptation and encourage your trainees and people in training to indeed apply the kinds of clinical acumen [that] I think we’d all love to have in relation to making these decisions?
Najib Rahman: Yes. I think it’s a great question, Paul. I’m quite obsessed with training this into our fellows. And I think we regard ultrasound as an adjunct to clinical decision-making. And we have to avoid being technicians. If we go down the route of saying “I can see it on ultrasound, I can put I needle into it,” then we’ve really divorced ourselves from our physicianly training, so I agree with that 100%. There is quality data out there suggesting that we do need to still use our clinical brains. The two examples I would use are left ventricular failure, as you’ve said, bilateral effusions [], it’s not going to be anything else. The other area where people make mistakes [] pleural pH and pleural infection. So [] expert believes that pH is a diagnostic criteria for pleural infection. It’s not, unless you are in the correct clinical context, and that requires some clinical acumen. Just to finish off, I think ultrasound has a particular danger where this is concerned: just because we can or can’t see pleural effusion doesn’t necessarily translate to why the patient is dyspneic. And one of the things we encourage our fellows to do is to add value to the patient. So if they go and scan the fluid, they’re still a respiratory physician, they should be able to comment on why the patient is breathless [although] they’re not going to insert a catheter.
Paul O’Byrne: Excellent. Thanks so much. Bram, a question directed to your presentation on the management of respiratory failure outside the ICU. I’d also actually value Wisia’s comments as well on this particular question. The question is, “Would you recommend a trial of high-flow oxygen therapy in acute COPD exacerbations with some degree of hypercapnia?” And the second part of the question: “What level of PaCO2 should suggest the use of non-invasive ventilation rather than high-flow oxygen therapy in such a patient?”
Professor Bram Rochwerg: Yes, thanks, Paul. And thanks again also for being included in this great panel. The discussion so far has been fantastic. You know, I think it’s a great question. The data looking at high-flow nasal cannula in the setting of hypoxemic respiratory failure is much better developed than the data looking at hypercarbic respiratory failure. And there are reasons to suspect that there might be some benefit and reasons also that it would obviously not be as good as BiPAP or bilevel ventilation, where… you know, with bilevel you get augmentation of tidal volumes, increase in minute ventilation dependent on that Delta P in the change in pressure between the inspiratory pressures and the PEEP. And certainly bilevel is better for accentuation of CO2 clearance. Now, that being said, with high-flow nasal cannula, with the high flows that are achieved, there is still recirculation of air and you do likely get an element of enhanced CO2 clearance, just [from the] nature of the high flows and circulating out of the dead space and improvement in CO2 levels. And many of us have probably seen at the bedside, applying high-flow nasal cannula to somebody with hypercarbia – and you do see an improvement in hypercarbia. It’s not in everybody, but I certainly will in certain folks give it a try, perhaps, and also sometimes [it’s] an opportunity to keep people on the ward because if I want to initiate non-invasive ventilation, that usually goes along with bringing them to a more monitored setting, but if there is somebody that I’m especially motivated to try to keep on the ward – whether that’s related to bed spaces [or] to the patient’s own goals of care – I will often try high-flow nasal cannula for CO2 clearance on the ward. The evidence base looking at this is growing. There was an RCT published recently, looking at high-flow nasal cannula and hypercarbic respiratory failure, which did show some benefits. It was from a European group, if I’m not mistaken an Italian group. So I think we are starting to see some small randomized controlled trials in this field. I expect that this going to be the next frontier of potential application of high flow in the setting of COPD exacerbation. Obviously, it doesn’t do the same to control dyspnea and shortness of breath as bilevel does and, you know, if there is a patient that is quite dyspneic, you probably will get more benefit from bilevel in that situation for offloading the diaphragms. But I certainly think that there is a role for high flow in more mild hypercarbia. [I’m] interested in others’ thoughts as well.
Jadwiga Wedzicha: Shall I come in, Paul?
Paul O’Byrne: Wisia, please do.
Jadwiga Wedzicha: You know, I completely agree with that. I think high flow is worth a go. There are patients who you see in the emergency department, I think some of these people may reverse very quickly. They may have been given too much oxygen for instance in the ambulance … or they may have had too much sedation for some reason. I think these patients are worth a go. I’m afraid I am rather old-fashioned; I did a lot of the original work on BiPAP and I think it’s a fantastic technique. As you say, it does reduce dyspnea, there are a number of other advantages. But I certainly think once the evidence base grows, and we get to know what level of hypercarbia we can go to – I think that’s what we need to know at the moment – then I think I will be much happier using it. At the moment I basically would not use it much above 7 kPa, or 7 x 7.5 or 51-52 mm Hg, in my view. But I don’t know what Bram would do in that circumstance. I would certainly go to BiPAP in anyone who is hypercarbic.
Bram Rochwerg: Yes, I think I agree. I mean, it’s hard to put an exact number but you know, maybe a pH of 7.15 or 7.2 and higher, I agree I would give it a shot. Anything more dramatic perhaps moving right to bilevel.
Paul O’Byrne: Could I also just extend a question a little bit, Bram? Because when you are making the decision around the clinical scenario, obviously looking at the patient and the setting and the availability of ICU beds and all of these other things come into play, but is there any evidence about potential unwanted effects of either approach that would concern you or maybe help you in a particular patient to make a decision?
Bram Rochwerg: I mean, I think it’s a great question, Paul. And I think I brought up in the presentation, I think, that folks’ biggest concern with high flow [is] perhaps twofold. One – these patients can be quite ill and I think high flow is reassuring to some degree: you start high flow, the patient is talking, looking at you, interacting. They don’t look that sick, but high-flow nasal cannula at an FIO2 of 70%, 80%, or 90% is completely life support. And we’ve all seen these patients, if it comes off even for a couple of moments, they are at risk of dying. So I think the one risk I always think is underappreciated with high flow is the false reassurance that this patient isn’t as sick as they truly are. And then, where was I going with number two… risk. The delayed intubation is the other big piece. And you know, I think I struggle with this as well. Maybe not specific to hypercarbia, but otherwise, you leave a patient with mild-moderate ARDS, [who] would meet the criteria for mild-moderate ARDS who is spontaneously breathing and generating tidal volumes of 10 to 12 to 14 mL/kg. If you believe in this self-induced lung injury physiology, that they might be inducing further lung harm through barotrauma and overdistention, is it better to leave them like that, delaying intubation, perhaps worsening airspace disease and inflammatory cytokine production in the alveolar units versus, you know what, just intubating these patients, sedating them, taking control of the tidal volumes, aiming for lung protective ventilation, and optimizing things from that perspective. And you know, that comes with risks in terms of sedation and intubation, and especially in COVID-19, Paul, I’ve wrestled with this in so many patients, to say, “Should I just intubate them and take over and vent them the way I want to vent them? Or should I let them spontaneously breathe and I’m not sure what sort of damage they are doing with these large tidal volumes and delaying intubation?” And I don’t think we have the answers to that yet.
Paul O’Byrne: Thank you, Bram. An excellent answer. I actually also have a colleague who is one of the organizers of the MIRCIM meeting, professor Roman Jaeschke from McMaster, who I know is on the line. And Roman is also an intensivist with a great deal of experience. So Roman, I’m saying this just to encourage you to chime in and ask any questions or comment if something catches your interest, particularly around this very important area in sustaining respiratory function and gas exchange during COVID-19.
Professor Roman Jaeschke: Well, thank you. If I can say one reflection which I have, it’s the speed of development of our thoughts over the last year. I remember a year ago, there were directives in some hospitals to intubate everybody who was on more than 5 liters of oxygen. And it was not restricted to Canada. We obviously [progressed] in understanding of physiology dramatically since then and Bram is our expert. So I will rely on him for the months to go.
Bram Rochwerg: Thank you.
Paul O’Byrne: Wisia, I have a question directed to you. And this one, I think, [is] a terrific question which I would be really interested in hearing your response to. “Do we have any good quality evidence for the influence of pharmacotherapy on the rate of decline in lung function in patients with COPD?”
Jadwiga Wedzicha: That’s an excellent question. Paul, you know enough about this as well. So, this goes back to over 20 years [ago], when originally studies were set up of inhaled corticosteroids in COPD – EUROSCOP and others. And basically, we never managed to show that inhaled corticosteroids can affect lung function decline. However, over the years, we had that many studies of LABA/ICS; we’ve had studies now of triple LABA/LAMA/ICS. No primary analysis has shown improvement in disease progression, but secondary analyses certainly have. Then once as well, I’m sure I said the phrase that if a treatment reduces exacerbations, [then] 25% of lung function decline is probably due to exacerbation, if not more. Then you do expect these therapies to have an effect on lung function decline. There is an anecdotal bit of evidence in that we are seeing less severe COPD around at the moment. Our wards used to be full of patients in hypercapnic respiratory failure. We are not seeing these people. I know there is less smoking – there’s number of other factors involved – but I believe we are, with inhaled corticosteroids and anti-inflammatories, preventing disease progression, but I cannot give you a trial with this as a primary outcome. Paul, do you agree on that?
Paul O’Byrne: Oh yes, absolutely. And in fact, to extend the question just a little bit, Wisia. Your original studies that were so impactful, at least in my thinking, in relation to exacerbation, risk of exacerbations, exacerbations occurring, and subsequent change in lung function over time in COPD and in fact made me do the analysis that we ended up doing in [], because of that original observation. So, that would imply that if you reduce exacerbation number or risk that you might preserve lung function, do you think there is any… is that realistic in your view?
Jadwiga Wedzicha: I think it is. And I think there is increasing evidence that exacerbations are not recovered to norm. Some do, in asthma they are more likely to recover; in COPD there is lots of other factors, there is remodeling mucus impaction and everything else. So yes, I am a very strong believer that exacerbations drive degree of disease progression. What I can’t tell you, Paul and everyone, [is] how much it actually is. When we did some calculations, [we came up with] 25%, interestingly, and NIH did similar calculations with [00:29:10] study. And also came up to around 25%, but they only had really data on infection, so I think this is getting important. We are all getting again interested in bronchitis. And of course, bronchitis makes you more likely to have exacerbation. So I think there is a triangle of bronchitis, exacerbations, and disease progression, Paul. I think those three things are probably closely… And then the other factors are emphysema and mechanical factors, to a certain extent.
Paul O’Byrne: So maybe I could also address the question to John. John, during your presentation, you talked about the vicious cycle in bronchiectasis. Is there evidence that acute exacerbations of bronchiectasis do result in more risk of subsequent exacerbation? And then of course, worsening structural change in the airway?
John Kolbe: I guess my response to that is very, very similar to the one that you’ve just heard. Again, I believe that patients with recurrent exacerbation seem to be those who have an accelerated decline in their lung function, but there is no really good quality evidence to support that. In recent years… you know, the vicious cycle hypothesis was put forward by Professor Peter Cole a number of decades ago and recently, there has been quite a lot of evidence that supports that hypothesis. And of course, integral to that is the fact that inflammation and infection leads to progressive airway damage and progressive worsening of clearance of secretions, etc. So, intuitively you would think that prevention of exacerbations may in fact lead to a reduction in progression of disease, but there is no really good supportive evidence for that.
Paul O’Byrne: Great. Thanks, John. Najib, a question directed to you – and I’m going to extend it just a little bit. The question being asked is, “Can we safely perform thoracoscopy in patients with respiratory insufficiency and respiratory failure, such as advanced COPD?” And perhaps to extend it a little bit, are there indications that you sort of use to decide not to do thoracoscopy in other clinical situations?
Najib Rahman: Yes, absolutely, thanks, Paul. It’s an important question, actually, because as thoracoscopy becomes less and less invasive, we are starting to extend the patient groups in whom we use this important technique. And it’s got an incredibly high diagnostic yield, as I said in my talk. Most of the time – 80% of the time or so within our practice – we have the opportunity to do a thoracoscopy very safely because the patient has a large effusion. So they have sort of shown us [] that they can manage on one lung. Of course, in the majority of cases, all we do is replace the large effusion with a large pneumothorax. In fact, their ventilatory parameters improve quite significantly, largely because we de-weight the diaphragm. So even if a patient has severe COPD, even – dare I said it – if they’re slightly baseline hypercapnic, if they’ve got a large effusion, I’m going to make the physiology better with my procedure and then it’s legitimate to do a thoracoscopy. Now, that’s the 80%. The problem comes when we start to push our limits a little bit and do what we call “dry thoracoscopy,” so in the situation of patients who have, for example, pleural thickening but no pleural effusion. And my clinical approach to that – as you can appreciate, Paul – is very different. So we are much more cautious. I will often do a baseline blood gas to make sure that they don’t have a raised bicarb, for example, and have some signs of ventilatory failure, because I will immediately make their ventilation worse when I induce a pneumothorax. So I guess that’s my general approach. Are there other features that allow us to triage them away from thoracoscopy? In my experience, if they do have significant obstructive lung disease or interstitial lung disease, sometimes the intrinsic lung pressure is such that when my pneumothorax is induced, I’m left with a very small operating space. And in this particular situation, I prefer that the surgeons do this with a dual-lumen tube because they can completely collapse the lung. And then the final, great contraindication is if the chest wall is too big; my trocars are 10 cm and unfortunately we do have patients who have chest walls that are greater than 10 cm. In that situation again, I refer to my surgical colleagues.
Paul O’Byrne: Excellent, thank you. And another question, Najib, is related to the comment that you had made during your presentation that doing thoracentesis using ultrasound reduces the risk of pneumothorax. Can you explain how that happens?
Najib Rahman: Yes, of course. So, that data is very solid now. We’ve got meta-analyses with 65 000 patients looking at with and without ultrasound and an odds ratio of 0.19 for pneumothorax, so it’s very solid data. What’s the mechanism? I guess there are two potential mechanisms. The first and the one that one wants to avoid is visceral pleural damage during insertion of the chest tube or insertion of the needle. An ultrasound very much prevents you from doing that in two ways. If you mark the skin, measure the distance from the parietal to the visceral pleura, you know exactly where the needle is all the time. In our hands, we tend to do things in real time. So we actually watch the needle is going to the pleural space and there is no change of lacerating the visceral pleura and creating an alveolopleural fistula. So that’s the first mechanism. The second mechanism is probably more subtle and is related to over-drainage of fluid and creating negative-pressure pleural space. Can ultrasound help prevent that? Well, there is some data that it might. So if I recognize, for example, thickened visceral pleural with ultrasound, I might more early in my thoracentesis terminate the procedure, in knowledge of the fact that this patient is likely to have a trapped lung. And then, finally, the most common cause of pneumothorax post-aspiration is air entrainment. That means that at some point I’ve taken my finger off the catheter and allowed air to go in. And that tends to occur in my experience less with a guided procedure, because one is very certain where the tip of the catheter is.
Paul O’Byrne: Excellent. Thank you very much, indeed. There is a question from one of the attendees today, and I’m going to direct it to Bram. The question is, “How long would you be willing to keep a patient with hypoxemic respiratory failure on high-flow nasal cannula? And what is the maximum concentration of oxygen you would be happy with before considering intubation and ventilation in such a patient?”
Bram Rochwerg: Great questions. And I think our comfort with this sort of thing has evolved over time, for sure, and perhaps [has been] accentuated in the setting of COVID-19 pneumonia, as well. You know, I think that it’s hard to pick a specific duration. And especially with COVID-19, I can think of a number of patients that I looked after on very high settings of high-flow nasal cannula for 2 to even 3 weeks before either experiencing deterioration and requiring intubation or improving. And I’ve had many patients with both. Some were on high-flow nasal cannula for a couple of weeks and then ended up deteriorating and requiring intubation. And I wrestled with that question: “Should I have intubated them sooner and limited ongoing lung injury?” And then I’ve had a number of patients that were on high-flow for 2 or 3 weeks and avoided intubation and went off of the ward and went home. I’m more certain in this situation I did the best that I could for them, having avoided the complications that go with sedation and invasive mechanical ventilation. So, you know, the good thing about high-flow compared to bilevel ventilation is it is better tolerated. And it’s better tolerated over long periods of time, so much [so] that patients can communicate, they can eat, they don’t develop facial breakdown and sores. So it’s not ridiculous to consider patients wearing high-flow for weeks at a time. That’s simply weighed against those risks of self-induced lung injury that we discussed and some uncertainty about whether delaying things could be harmful. In terms of maximum FIO2, you know, the benefits of the high-flow is you could achieve almost close to an FIO2 of 100% with high-flow, maybe in the range of 90[%] to 95[%], at least. And in addition to self-induced lung injury from volumes, we also worry about things like oxygen toxicity and free radical production and the impact that this might have on the lungs. But again, this is weighed against the risks of the alternative, which is often sedation [and] intubation. And these are careful evaluations. In the setting of COVID-19, specifically in patients that were scared of intubation and wanting to push it off as long as possible, I’ve had patients on 95% high-flow with then a non-rebreather mask over top and trying to maximize oxygen delivery as much as possible. And I’ve had a few of those patients that never ended up requiring intubation. So, there really is no maximal limit; there’s just a balancing of pros and cons and similar in terms of duration. It all comes down to a balance of weighing those risks against those benefits. [I’m] interested, again, as always, if others with expertise here have input too.
Paul O’Byrne: Any other comments? It’s very comprehensive answer, thank you. And maybe another question directed to you about using noninvasive ventilation using helmets. Any advantages over masks, except for infection control?
Bram Rochwerg: Yes, it’s interesting. At my own institution, I pushed hard and we purchased 100 helmets from a company in Italy. They had just received approval in Canada on the heels of COVID-19 and we’ve been using them in both COVID-19 and non-COVID-19 patients for delivery of noninvasive ventilation. And we’ve certainly seen some benefits. You know, I described the biggest complications of bilevel, for those that have used it, in terms of facial skin breakdown, which is a very real complication. Patients that wear BiPAP for a long period of time – their face melts and you start to see ulcerations and problems, which is a big concern. And then the ability to eat, talk, [and] communicate is limited. So, the helmet – you know, it looks like a space astronaut helmet – really gets around some of these complications and we’ve had patients both with COVID-19 and without COVID-19 tolerate bilevel ventilation for longer periods of time using the helmet as compared to the alternative. I’ve even put the helmet on some of my ICU fellows, just to trial it and see. They seemed to tolerate it as OK and said that it’s actually not that uncomfortable compared to what I see with patients wearing the face mask. In addition to this case-based experience, we’re increasing our RCT database looking at the helmet. There was a head-to-head trial by Patel in Boston looking at face masks versus helmets published in JAMA in 2016, which showed a potential signal for less intubation in those using the helmet. And corroborated findings recently published in JAMA, specifically in COVID-19 patients, that compared the helmet versus high-flow nasal cannula and showed less need for intubation in those wearing the helmet. So [it’s] interesting to think – 5 years down the road, 10 years down the road as uptake and evidence builds with the helmet – whether this could be our new standard interface for bilevel delivery? It might be. I think we’re going to see, I think we are still in the early adoption phase and we’re going to see more widespread uptake as the research phase builds, both in hypoxemic respiratory failure and in hypercarbic respiratory failure.
Paul O’Byrne: Terrific. Thanks so much, Bram. John, a question directed to you. Which investigation should be considered for a newly-diagnosed elderly patient with bronchiectasis? Now, I have to say I do not know how to define “elderly” anymore – other than 5 years older than me – but I’ll let you use whatever discretion you would like in deciding who is elderly. And should we modify examination suggested by the EURES guidelines in these elderly patients?
John Kolbe: Thank you, Paul. That’s a very good question because in my talk and in some of the guidelines, there is a list of the investigations that should be undertaken. And the question is, in the clinical setting, should all of these investigations be undertaken in all patients? And in particular, should you modify your approach according to the patient’s age or perhaps co-morbidities? I would certainly measure immunoglobulins. I think that immunoglobulin deficiency and the correction of this can have massive beneficial effects for the patients. So I would always do that. Especially in patients who have airflow obstruction, I would look for criteria for the diagnosis of allergic bronchopulmonary aspergillosis, because I think that too has quite a lot of clinical significance. I think that will influence how you manage the patient down the track. Would I do a sweat test on a patient presenting at my age? I have to say the answer to that is no. They clearly, if they are presenting at my age, they clearly have mild disease. Another thing is that I am not sure that giving a patient that label late in their life necessarily is to the benefit of the patient. And we have a number of patients in whom we or others have been proud of the fact that we have been so clever to make the diagnosis of cystic fibrosis at a later age, but I am very skeptical we have actually done well by the patient. So I would not do that. I would not use nasal nitric oxide to screen for primary ciliary dyskinesia. I would make sure that the patient doesn’t have an underlying connective tissue disease or inflammatory bowel disease, because I think once again that has potential therapeutic implications.
Paul O’Byrne: Perfect. Thanks so much, John. Wisia, a question to you. And the question is about measuring blood eosinophil count in all patients with COPD or severe COPD. Would you only do it in those with other potential indications for inhaled corticosteroid use?
Jadwiga Wedzicha: So an interesting question, good question. Should you measure blood eosinophils in everybody? Well, I think if a patient doesn’t have exacerbations, if this is the first time we meet them, they are not on any treatment, [then] technically you don’t need the blood eosinophil count, because your first treatment these days will be a dual bronchodilator. I think we’ve got good compounds, once daily, and importantly – from the cardiovascular point of view – they are safe. However, later on these patients will develop exacerbations. And I think it’s very important to phenotype patients as early as you can. That is what I would do. The other thing is that we need to learn more longitudinally about what happens to eosinophils over time. My hypothesis would be as patients develop exacerbations, the eosinophil count increases. There is a link between viral infections and inflammation in eosinophils. So I think, yes, the answer is [that] I would measure it, but it is primarily an indicator of inhaled steroid response and sensitivity.
Paul O’Byrne: Excellent. Thank you, Wisia, that’s terrific. Bram, there is a question coming from one of the audience [members] today. That is: “How often do you observe pneumothorax as a complication of noninvasive ventilation methods? Or using high flow?”
Bram Rochwerg: So you know, any time one undergoes positive pressure ventilation, macroscopic barotrauma is a risk – [it’s] certainly a possibility with bilevel ventilation – [but] probably a little less so than those on higher pressures of true invasive mechanical ventilation, because there is also an element of spontaneous effort and negative pressure from the patient, which probably staves off barotrauma. And it’s more the positive pressure from the machine that causes pneumothoraces. So in general, with bilevel ventilation, there is a risk, but I’d say [it’s] more rare compared to invasive mechanical ventilation. With high-flow nasal cannula I think that risk is even smaller. Again, you know, [with] the flows that are achieved in a range of 60 to 70 to 80 L/min, it doesn’t generate enough pressure generally to cause barotrauma. I have in my editorial activity seen case reports of COVID-19 patients on high-flow nasal cannula that developed pneumothoraces; whether this was related to the high-flow nasal cannula or related to the underlying disease or others is always going to be impossible to tease out, but in general the risk of high-flow nasal cannula, I’d say, is extremely low compared to other modalities of noninvasive support.
Paul O’Byrne: Thank you very much, Bram. Najib, a question related to the complications of thoracentesis and withdrawing fairly large volumes of fluid. During your presentation, you said you would often take off 1 [or] 1.5 L of fluid and I personally thought the demonstration of diaphragm and the position of the diaphragm is extremely convincing in relation to understanding the mechanisms of dyspnea with pleural effusions. But when I was younger – this was a long, long time ago – there was a concern about re-expansion pulmonary edema if you took off too much fluid too quickly. Is that a real risk or should we ever be concerned about that?
Najib Rahman: Yes, that’s a great question, Paul. So, re-expansion pulmonary edema is real. I’ve seen patients die of it; most respiratory physicians have seen patients die of it. And we regularly find it in our practice, thankfully not that regularly, so it’s definitely a real phenomenon. It would be interesting to debate what the causes of that are; perhaps we will get to that a bit later. How do we prevent it occurring? Well, we think it is a response to reperfusion of a lung that has been de-perfused for a significant amount of time. And there is certainly some soft data that the longer the lung has been down under the pressure of effusion or pneumothorax, the more likely that reperfusion injury is on re-expansion. Very interestingly, if you do a CT scan immediately after a thoracentesis in a completely well patient, almost universally you find a degree of parenchymal lung infiltrate. And so the concept of radiological re-expansion pulmonary edema is not the same as that clinical one that you recognize, which is hypoxia, and the patient is at death’s door. In my practice, we tend to continue the thoracentesis until the patient experiences one of two symptoms: one being a recurrent, difficult-to-move cough and the second being central chest pain which we described as mediastinal shift syndrome. So the idea [is] that you are developing a negative pressure within the pleura and the mediastinum is shifting towards the side of the thoracentesis. If one measures and carefully conducts the thoracentesis with an assessment of symptoms, I think re-expansion pulmonary edema can essentially always be prevented. I will just add one piece of data to this. So David [00:50:45], who was at Johns Hopkins at a time, did a great series of 200 thoracenteses and they took off up to 6.5 L in patients, depending on symptoms. In that 200-patient set, they had 1 episode of re-expansion pulmonary edema and that was in a patient where they took 1 liter. So unfortunately, this is just a surprising complication, but one that can be prevented with a skilled thoracentesis if you stand by the patient and watch them for symptoms.
Paul O’Byrne: Excellent. Thanks very much, Najib. John and Wisia… maybe I’ll direct the question to John. John, during your presentation, you talked about novel approaches to treating bronchiectasis. And I was going to ask you the likelihood that this is going to be an advance, in your view. But also [I would] ask Wisia about novel approaches to the management of severe COPD. As you know, in asthma we now have at least 5, maybe soon to be 6 biologics with various mechanisms of action that are available to treat severe asthma. What’s the future looking like for COPD and bronchiectasis?
Jadwiga Wedzicha: Shall I go first? John is quiet. John, are you going first? OK, ladies first. We’ll do COPD first. Well, I think COPD has been a disappointment, Paul. A number of interventions had been tried. I think we were hopeful that anti-IL-5 biologics would work. So far we haven’t got a biologic that works in COPD. Though there again, we need to look at specific phenotypes, and patients with high eosinophil counts, I think, may well respond to IL-5. There are interesting others on the agenda. But I think one… I mentioned bronchitis already. I think mucus is an interesting factor and one that is of interest to drugs developers. So we’re at the moment at Imperial conducting a study, and with others, with CFTR potentiators. So there are abnormalities of CFTR in COPD and it would be very interesting to see what happens. The pilot data looks good, so we now have to try it. So I think today it’s been very disappointing; we’ve not had many novel compounds, but I think we need to think out of the box and look at different phenotypes to tackle.
Paul O’Byrne: Thank you, Wisia. John?
John Kolbe: If I was to have given a talk on the evidence-based management of bronchiectasis 10 years ago, it would have been an exceedingly short talk. And I introduced into my talk a couple of slides that, if you like, were teasers to give the audience some indication of where the management of bronchiectasis may go in the future. I provided that data on [] inhibition because that represents quite a different approach to the whole management of bronchiectasis. Previously, we were looking at ways to augment, if you like, the immune response to control the infection and with the view that we would be inhibiting that vicious cycle of infection that I outlined. The approach with that new agent is to say that we actually have an augmented inflammatory response in bronchiectasis – and in fact, that is responsible, at least in part, for the lung damage; I used the term “collateral damage.” And so this was a different way of, if you like, modulating the body’s immune response to what’s going on in the lung. And I thought that that was an interesting and intriguing approach. I also talked very briefly about the use of nebulized hypertonic saline, for which there is very limited evidence in bronchiectasis as compared to that in cystic fibrosis. But in the introduction to that treatment, I provided some information on some recent studies looking at the mucus in bronchiectasis and I hope the audience appreciated the fact that actually the changes or the abnormalities in the mucus in bronchiectasis were much more similar than previously thought to the abnormalities which are demonstrated, for example, in cystic fibrosis. So might there be in the future a role for agents that influence ion and water transport across the respiratory epithelium and thereby influence the physical and other properties of the mucus? And I will just throw out there that, you know, we are in a process of looking at small interfering RNA directed at the sodium channel in the apical portion of the respiratory epithelial cell. And that’s in the context of cystic fibrosis, but in fact that drug could potentially have beneficial effects in bronchiectasis, based on the evidence, or the abnormalities that we see in the mucus. So, I think there are number of exciting avenues that we can see right now for the management of bronchiectasis, so I think it’s an exciting time in this condition which actually has been neglected for decades up until I guess the last 10 years.
Paul O’Byrne: John, thank you very much. And this hour has flown by. We are out of time, but I want to thank each of you for absolutely outstanding presentations and for participating in this very, very high-quality discussion. Thank you all. Thank you to the people who have attended and provided questions to us. And to the MIRCIM organizers, as always, for such a wonderfully organized series of meetings. And let’s hope, fingers crossed, next year [it will be] in Krakow: that should be our cry. So thanks everybody and have a good rest of the week.
John Kolbe: Thank you very much, goodbye.
Najib Rahman: Thank you, Paul. Bye, bye now.
