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>> Howard Bauchner: Hello, and welcome to Conversations with Dr. Bauchner. Once again, it is Howard Bauchner, editor-in-chief of JAMA. You will all have to constrain my exuberance about doing this livestream. I am so excited. I am joined by Domenico Luca Grieco, who is the author of a gem of a small randomized clinical trial entitled The Effect of Helmet Noninvasive Ventilation versus High-Flow Nasal Oxygen on Days Free of Respiratory Support in Patients With COVID-19 and Moderate to Severe Hypoxemic Respiratory Failure. And the two co-authors of the accompanying editorial, Laveena Munshi from Toronto and Jesse Hall from Chicago, Respiratory Support During COVID-19 Pandemic. Domenico, you're my second Italian guest. I want to remind the listeners, my first was Maurizio Cecconi, who I interviewed almost one year ago on March 13th, when he sadly and profoundly announced to the world that we had no idea what was coming. I'm so happy to welcome you here. This is a small clinical trial, just over 125 patients, randomized to a helmet -- and we'll be able to show you a picture of what that look like -- versus high-flow oxygen to prevent a primary outcome and then a number of secondary outcomes. The study was conducted between October and December. And the reason that's important because they all receive standard of care, what has become standard of care: corticosteroids. So, Domenico, can you explain the study and what prompted you to do it?
>> Domenico Grieco: Morning, and many thanks for the invitation to join you. It's a great privilege to be here today and to present. So what we essentially did is that we enrolled patients in the intensive care unit experiencing hypoxic respiratory failure due to COVID-19 within, let's say, 48 hours from hospital admission, so in the very early phase of hypoxemic, respiratory failure. And we randomized patients to receive either what we, let's say, consider the standard of care recently outlined by clinical guidelines, which is the high-flow oxygen delivered by nasal camera, which is really easy to use at the bedside for every physician, and it delivers 60 liters of air-oxygen mixer to the patient at a continuously heated and humidified gas. This was the control group, and the intervention group received continuous treatment, so early continuous treatment with the helmet NIV with relatively high pressure end-expiratory pressure and relatively low pressure support. So PEEP, which is the positive end-expiratory pressure of 10, 12 centimeters of water, and pressure support of 10,12 centimeters of water. That are somehow weird settings, but are those that we showed to be effective in relieving the inspiratory effort and improving hypoxemia in hypoxemic patients in a previous physiologic study published last year. And the primary endpoint was the proportion of days in which patients did not receive any form of, let's say, advanced respiratory support so the kind of support for which an ICU is needed, so high-flow, NIV, or invasive mechanical ventilation on a 28-day basis. So there was no difference in the primary outcome, but we found that there was a significant reduction in the amount of patients who required endotracheal intubation and invasive mechanical ventilation. So it was 50% versus 30%, so a significant reduction which yields number needed to treat of five, which is quite low considering the amount of patients that we are treating. And this finding was somehow consistent with the physiologic data we have on the benefit of high PEEP in spontaneously breathing patients, and it seems somehow promising for a technique which is not very common in places outside Italy.
>> Laveena Munshi: Laveena, when I sent you the paper to review, when you read it, did you light up? You know, people have like pre-test -- Do you like studies? Do you not like studies? What was your reaction when you first read it?
>> Laveena Munshi: So, first of all, thank you for having me, and congratulations, Domenico, on the study. I was very excited and enthusiastic to read it as soon as I saw the title. There's been a lot of enthusiasm on this side of the ocean, I think, for the potential role of helmet noninvasive ventilation, and particularly in comparison to high-flow nasal cannula because, to my knowledge, I think this is the first head-to-head comparison in an RCT. So I was I was very excited just because I'm intrigued by the potential role after Dr. Patel's study and Dr. Hall's study that was published a few years ago. And then, because of the fact that it's COVID-19, there seems to be this, I guess, need to better understand the potential of all the different noninvasive strategies, so this was definitely timely. And I think it's important to understand the role of not just from a patient standpoint with regard to reducing the risk of intubation, especially at the beginning of the pandemic when we heard of mortality rates, but also from a health system standpoint, given the concern about capacities in our ICUs. So I was definitely really excited about the study when I had the invitation to review it for sure.
>> Howard Bauchner: Now, Jesse, you're one of the world's experts in the use of the helmet. You've written for JAMA. And for our listeners, I just really want to thank all of the reviewers, but both Laveena and Jesse reviewed the paper in two or three days. I think we only received it two and a half or three weeks ago. Jesse, when you got the paper, what did you think? I mean, you've been working at this for, I don't know, a decade or more.
>> Jesse Hall: Yeah. Well, thanks for inviting me. And Domenico, I add my congratulations to you and your colleagues. I'm one of the people outside Italy that have learned so much from the Italian investigations involving this new interesting interface for patients. So yeah, my first reaction was overlapped with some of the things Laveena said. I knew there had not been a really good head-to-head comparison of the helmet to high-flow nasal cannula treatment. So just that by itself, whoever the patients were, sort of tweaked my interest. Next, as I started to look at it and see how rigorously it was done, my hat was off to this group because, on the one hand, it's so important to get studies done in this setting, and the results are so important to us. On the other hand, it's about the toughest environment when your ICU is being overwhelmed, or potentially so, to do such studies. So the fact that the study was so well done under extreme conditions sort of just had my admiration, and you're not going to see that very often. So that just, you know, hooked me, I guess, and then I kind of got into the details of it. And like all studies, it sort of fits in a flow of learning that, you know, you wish you had some other results, but you got some interesting, intriguing results, and now you have to kind of put it into the larger realm of further study as well as current clinical practice. So I was I was hooked and thought this was an important trial.
>> Howard Bauchner: Domenico, just following up on what Jesse said, was it hard to do the study? You know, you're overwhelmed. You're taking care of patients, many of whom were dying. The ICUs are really busy. And you say to a clinician, "Well, do you mind if I bother you a little more and randomize patients?" Not easy. And we've had many conversations on this show about trying to generate high-quality evidence. Was it hard to just do the study in the ICUs?
>> Domenico Grieco: It was a little bit, I have to be honest, and I want to share my thanks to all the coauthors and collaborators, were a lot, and this is why there are a lot: because it was not easy. We can remember patients randomized at midnight or 2 AM in the morning, so phone calls and patients randomized in the web system, so it was not easy to do. But I think that, thanks to the collaborative group, when you put all the efforts together, we managed to do that during the second wave because the study was launched essentially at the same time the second wave started in Italy. So we had a strong wave and, honestly, we were used to using the helmet in the first wave and since years. But it was not easy to randomize patients to receive one treatment or the other because sometimes you need to balance these with the attitude of the physicians, and sometimes they felt like that equipment was not proper. So I think this is an issue with all randomized control studies in which you randomize patients, but we need these for generating evidence and to extending the knowledge we have on patients. What really surprised us, for instance, is that there was a huge difference in the rate of endotracheal intubation when there is no change in mortality.
>> Howard Bauchner: Right.
>> Domenico Grieco: Let's say absolutely the same number, so it's 24%. So, and this reassured, for instance, a lot of us saying, okay, the high-flow is safe. It's not really -- Okay, maybe the helmet allows you to avoid intubation in a certain amount of cases, but if you do not have the expertise, you don't have the tools to use this technique in the ICU because we need monitoring. We need to look after the patient with maybe a good nurse-to-patient ratio. The high flow is a really good alternative. So this really reassured us also for the treatment of all the patients that came afterwards.
>> Howard Bauchner: Laveena, you and Jesse both write quite a bit about, you know, primary outcomes shows no difference, secondary outcomes, you know, people talk about alpha spend and then whether or not you consider it exploratory or not. Let's put kind of the methods and statistical language aside, because the both of you, then, write about how you're now thinking about this, whether you have experience or not, and what it means. How have you thought about since the paper was published? It's published as we speak, but since you read it.
>> So yeah, I feel like certainly intriguing, and I'm very excited to better understand its potential role as one of our devices now in the treatment of acute respiratory failure. So as Domenico highlighted, no difference in primary outcome of respiratory free days. And while that may be an important outcome from a system standpoint, particularly during a pandemic, I think future research really needs to focus on how the different oxygen devices may impact better patient-centered outcomes, such as fully reevaluate intubation and then further explore this outcome of mortality, and other patient-centered outcomes, such as cognitive function, functional outcomes following ICU. And I think what's very interesting is that I think, at the end of the day, as we design these further studies to further evaluate the noninvasive oxygen strategies, we need to be smart about exploring and understanding the different respiratory failure phenotypes because what we may discover is that it's not a one-size-fits-all approach. It may be that, in a subset of patients, they may do well with high-flow nasal cannula. In another subtype of patient, they may do better with more recruitment and the helmet interface. So I think, at this point, we need to better understand its role and, in the design of these trials, be smart about thinking through the different phenotypes of respiratory failure, and then maybe understand which subtypes have the greater response to one modality or another.
>> Howard Bauchner: Jesse, as I've already mentioned, you've been at this a long time. Does this move the dial for you around helmets?
>> Jesse Hall: It puts my hand on the dial and maybe slightly inclined in one direction. The business about the primary endpoint, you know, not being met, it turns out to be, in part, a power issue right because earlier data, you know, suggested a good power calculation and they'd be able to determine if this was helpful for a large population of patients that would, therefore, get less respiratory support and, therefore, perhaps go through the system and be returned to health sooner. That's good from a public health point of view. As it turns out, there was less support needed. This got back, in my mind, to your earlier comment that, if the standard of care is such a rapidly moving target, maybe with steroids now, we actually know one of the effects is reducing the amount and severity of respiratory failure. So that's great that we now have that plugged into this study, but then your power calculation may need to get adjusted. For the issue of reducing the amount of intubation, I have a strong bias that that's just a good thing. Now, I know there could be arguments about, maybe it's not as good thing as we think, and those are kind of, you know, for critical care pro-con debates down the road, I'm sure. But, in my thinking, it has usually been good when we have spared people mechanical ventilation invasively. And even if mortality didn't change, I would be very interested in what happened to long-term outcomes for patients because getting an endotracheal tube and surviving the ICU experience usually is associated with your course being protracted and difficult to fully recover. And it somehow, I really think that it would merit study to see, if all you did was reduce the rate of invasive ventilation, that in and of itself, apart from mortality, could still be a very good thing.
>> Howard Bauchner: Domenico, a couple questions have come in. What was the neurologic status of the patients?
>> Domenico Grieco: All patients were fully awake. They were really more dyspneic than we were expecting. You know, we have learned that sometimes these patients experience signs of hypoxemia, but dyspnea score was, like, on average, because it was consistent with the data we have for hypoxemic respiratory failure of other etiologies. But they absolutely were fully awake. We left to the choice of the clinicians the use of sedatives and analgesic drugs. This is somehow a weakness of the study because they were not standardized. We have data showing that, on NIV, the combined use of them may be associated failure, but we tried to leave the choice about the use of sedative analgesic drugs with treating physicians. And it was more common in the NIV group, and I think this was unavoidable because we have to admit that is less comfortable than high-flow, and it has shown us in this comfort scale, which is improved, which is worse in the NIV group. But patients were fully completely awake until the required intubation, yeah. And nobody required intubation due to a -- saw dramatic change in the mental status, which is a concern about the use of helmet NIV possibly about CO2 re-breathing and things like that [inaudible] about this.
>> Howard Bauchner: Oftentimes, when people write editorials for us, they go, "Could you just ask the author this question? I'm just curious." Because there's not usually an exchange between editorialists and authors of papers. But Jesse and Laveena, now you have a chance to ask for some more details, or "Did you really do that?" I'll start with you, Jesse. Do you have a question for Domenico about the study?
>> Jesse Hall: Thanks, Howard. There could be many. But one large difference between the group was the ability to prone some 60% of the high-flow patients and 0% of the helmet patients. Can you think about that with me? You know, tell me if that's just a condition of the therapy in your hands, and you folks are more experienced than anyone. And if it's just how it goes as a support treatment, is it an important difference between the two groups that one can be prone and one cannot? Because, as you know, there's sort of proning literature predating COVID and continuing right on through the management of COVID patients.
>> Domenico Grieco: Similarly to the analgesic drugs, we left these open to the physicians, which is, I think, both a strength and a weakness of the study because the strength is based on the fact that helmet NIV may reduce the rate of endotracheal intubation as compared to high flow combined with prone position, which is a strength of the intervention. And this is also a weakness because the two groups were not balanced regarding this intervention. And we left it open, and clinicians happen to use more frequently this tool during high flow. So I think there are two main reasons. One is that hypoxemia is more relevant during the high flow because the PF ratio in the helmet group is higher than the one in the high flow group, which could be a first cause. So there was less feeling for the need of rescue treatment because the way it was used, this was kind of rescue treatment. And the second reason is that it's much easier to prone the patient with the high flow than with the helmet HIV. And we know that this is interesting because this is something which is really pragmatic. So we know that patients in the high flow group are more easily proneable than those in helmet.
>> Howard Bauchner: Laveena, your questions?
>> Laveena Munshi: Yeah, I actually have two. So the first one actually surrounds tidal volume. So, as you know, from the facemask noninvasive ventilation literature, one of the concerns is that, when it's applied across higher severities of respiratory failure, it's associated with a high risk of failure and potentially high mortality. And one of the mechanisms that's described is that the facemask noninvasive ventilation may lead to high tidal volumes and injurious tidal volumes. In your helmet population, I know it's challenging to measure tidal volumes through the helmet interface. If you look at just the subset that got intubated, there was a higher mortality just in helmet, which is likely just due to the fact that they have a higher severity of illness. But what do you think about the theory of helmet potentially inducing injurious ventilation through high tidal volumes? Is that something that you guys discussed or were concerned about at all in your population? And then did the sedation that you applied, was part of that sedation to potentially blunt that effect?
>> Domenico Grieco: This is a very good question. We would be delighted to have some physiologic measures like inspiratory effort or the tidal volume during helmet NIV. We did not. We could not because in the setting of a randomized trial in such an emergency context, it was not easy. We had data showing that, indeed, the entity of inspiratory effort during helmet NIV is associated to the risk of endotracheal intubation. I think that this could be -- This is possible also in the context of COVID-19 respiratory failure. We need more data, but I think that this reinforces the message that what we have shown is that the intervention which is capable to reducing endotracheal intubation is not only the application of helmet NIV in a continuous fashion in the early phase of the disease but the strict monitoring we applied. So I think that the message for the ICU physicians worldwide should still be about caution in the use of any noninvasive tool just to monitor patients, to identify a treatment failure, and to deliver prompt intubation and protective ventilation in case treatment failure is identified. We try to use standardized criteria which can be applied, which is similar to those applied in the [inaudible] study. It's the one published in New England some years ago about high-flow in the JAMA and the helmet NIV - face mask NIV, I'm sorry. And I think this can be applied also in other ICU to identify treatment failure. And for sure, these are not physiologic measures like the one we're researching, but still it's something that can be applied to the bedside.
>> Howard Bauchner: Laveena, did you have a second question?
>> Laveena Munshi: Yeah. So have the results of this trial changed your day-to-day practice in your decision-making about the application of helmet versus high flow?
>> Domenico Grieco: This is really difficult to respond. I think that, in fact, one single randomized trial cannot change the clinical practice, but I think it's another break in the wall of knowledge. But we were fearing what you were saying. So in the first wave, we largely used the helmet NIV, and we were always concerned about the risk of delaying endotracheal intubation. So we wanted to respond whether the intervention that we were applying in the clinical practice could be useful for the patients. And so I don't think we are changing our clinical practice in our centers and thinking about the centers that participate in the trial. I think that we are continuing in the clinical practice we were at in the last six months, but we have been reassured that this intervention could be beneficial for patients. And we did not add clinical data about the comparison of these two techniques, so we're not sure that what we were doing was something good for the patient or not. And I think this data reassured about the use of helmets in the context of a pandemic, for sure, but early identification of treatment failure, this could be something good for the patient.
>> Howard Bauchner: Jesse, I think it's fair to say you've been around a little longer than the other two individuals who are on this call. [Inaudible] I'm trying to figure out the nicest way to say that, Jesse. Anyway.
>> Jesse Hall: That was kind.
>> Howard Bauchner: Okay, thank you. You know, there's always an issue of technology creep in medicine, particularly in the United States. United States is superb at technology creep, probably better than any other country. We are very good at it. You know, there's not a mortality difference. You raise the issue -- you think, in general, it's better not to receive mechanical ventilation. I never have outside of the need for anesthesia, so I imagine most people would agree with you. We're never going to have a 500-patient RCT of helmets. I just can't imagine that, or 1,000 patients. This was such a unique opportunity, such a homogeneous presentation, at least of a single viral disease. I know it has different manifestations. So, assuming we don't have that 500 or 1,000-patient RCT and, you know, we have a few studies, including yours and this one, what's the next three, four, five years look like for this technology?
>> Jesse Hall: Well, we certainly suffer from technology creep sometimes. You know, we just create a tool and then look for some place to start hammering away with it, and I get that. This, in a way, to me, is a little bit of -- It's a tool that also allows a deceleration of care that is invasive, and so that I keep a more careful eye on. There's a learning curve with the technology. You have to be good at it to be safe with it. But in some funny ways, it's backing off the advance of life support treatment that carries substantial risks that we know from decades of use. So I suppose you could say, well, it's something different than an endotracheal tube technologically. It's, you know, bigger, more involved, and you have to learn how to apply it. But we had to learn how to place endotracheal tubes, too, and they carry such risks. So if we have something less invasive, you know, I think we need to continue to work with it to see what patient populations can benefit from it. And some of the things that Laveena and I wrote about in the editorial, and the authors commented on in the paper, is that there could be subsets of patients for whom this is, in fact, ideal. We didn't talk too much about that, but PEEP is, you know, the critical lung recruitment tool in acute hypoxemic respiratory failure, whether you have an endotracheal tube or a mask interface of some sort. And so maybe the people that are PEEP responsive should get this. So Laveena and I tried to make a point that it's good to have these tools in your armamentarium as long as, number one, you know how to use them safely; number two, you have a careful eye to figuring out who will benefit from them. And it's probably not everybody. You know, looking for the, you know, 5,000 or 1,000-patient trial that tells you, okay, put that technology away and accept this new technology en toto. Like, I think that's fanciful. But being wise about a set of tools in your kit as an intensivist, I think, is wise.
>> Howard Bauchner: Laveena, do you think, over the coming years, you'll urge the purchase of more helmets in your ICU?
>> Howard Bauchner: So maybe just to go back to your previous statement about not necessarily seeing the 500 or 1,000-person trial, I think one of the most amazing, positive things about this pandemic that I think we've all probably spoken about at some point has been the collaboration that we've been able to achieve and establish across the critical care community. And I feel like we're probably all closer as critical care researchers. So I actually think that it is plausible that we could have the 500 or 1,000-person trial of helmet versus high-flow nasal cannula. But as Jesse alluded to, I think, in the process of designing that, we need to be smart about trying to tease out who are the subgroups that are going to respond to one intervention versus the other because there's probably heterogeneity of treatment effect here. So I do think it's possible. Helmet has just recently been approved by Health Canada. That's why we don't have big helmet programs in Canada yet, but we have applied, and our institution does have some funding to further evaluate the potential role of helmet compared to high-flow nasal cannula. And in the design phase, we're trying to be smart about trying to really tease out those differential subgroups that may benefit or not. So yes, I think we're going to see start to see more helmet in Canada, and I think we really need to focus on which is the subgroup that would benefit from it.
>> Howard Bauchner: Domenico, I'd like to give you the last word. As I said, all the COVID-19 papers have been triaged to me. I mean, for research, I've looked at thousands of papers, and I just felt, when I read this, it was a gem. I just really liked it. I mean, big RCTs are nice: 3,000, 4,000, 5,000 that you see in the cardiology world, occasionally in the intensive care unit world. But sometimes, these smaller studies are nuggets. So I'd like to give you the final word.
>> Domenico Grieco: So really, thanks for these words, and thank you very much. So I think that the future of -- I fully agree that the future of research on this topic is try to individualize subgroups of patients that may really benefit from one treatment or the other. Maybe there are some patients who only need flow, so the increase of the oxygen amount that they are receiving, and there are others that really need the amount of pressure maybe to control the inspiratory effort. One idea could be that patients with the intense inspiratory effort, they need something to relieve it. So maybe they need helmet NIV. We saw that our patients in whom the inspiratory effort is not high, they are completely calm, and they do not experience these huge tidal volumes that Laveena was mentioning. Maybe in these patients, the optimal tool is just to increase the amount of oxygen they are receiving, so they use high flow. I fully agree that the future of the research on this topic is, yes, conduct randomized control studies, but just to identify the patient population in which the interventions may work better.
>> Howard Bauchner: This is Howard Bauchner, editor-in-chief of JAMA. And, in some regards, this conversation represents something Laveena said, which is international cooperation. Jesse Hall is from Chicago. Laveena Munshi is from Toronto. And the author, Domenico Luca Grieco, is from Italy. We've been discussing the paper, The Effect of Helmet Noninvasive Ventilation versus High-Flow Nasal Oxygen on Days Free of Respiratory Support in Patients With COVID-19 and Moderate to Severe Hypoxemic Respiratory Failure, the HENIVOT randomized clinical trial. And it's been accompanied by an editorial, Respiratory Support During the COVID-19 Pandemic: Is It Time to Consider Using a Helmet? And I would be remiss not to say hello to the senior author, who's a very, very close friend, Massimo Antonelli, who I think chaired the study group. To the three of you, I say thank you and stay healthy, and thank you for your extraordinary clinical care you've given in the last year.
>> Jesse Hall: Thank you, Howard. Congratulations.
>> Domenico Grieco: Thanks.
>> Howard Bauchner: Bye, everybody.