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E8: Submerge-Paper Deep Dive: NIPPV for COPD exacerbation (HAPPEN Trial)

• Mohamed Hagahmed

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🚑 PICO Breakdown: The HAPPEN Trial on NPPV for COPD 🫁

P - Population:
Patients with acute exacerbation of COPD and persistent hypercapnia (PaCO₂ > 45 mmHg) after 6 hours of low-intensity NPPV.
👥 300 patients (Mean Age: 73 years, 68% Male)

I - Intervention:
High-Intensity NPPV - Tidal volume of 10-15 mL/kg using higher inspiratory positive airway pressure (IPAP).

C - Comparison:
Low-Intensity NPPV - Tidal volume of 6-10 mL/kg using lower IPAP.

O - Outcome:

  • 🌟 65% ↓ Risk of meeting criteria for intubation (4.8% vs. 13.7%, p=0.004)
  • ❌ No significant difference in actual intubation rates (3.4% vs. 3.9%)
  • 🤢 More abdominal distension with high-intensity NPPV (37% vs. 25%)

💡 Clinical Pearl:
High-intensity NPPV may delay progression to severe respiratory failure but requires careful monitoring of side effects.

Reference: Luo Z, Li Y, Li W, et al. Effect of High-Intensity vs Low-Intensity Noninvasive Positive Pressure Ventilation on the Need for Endotracheal Intubation in Patients With an Acute Exacerbation of Chronic Obstructive Pulmonary Disease: The HAPPEN Randomized Clinical Trial. JAMA. 2024;332(20):1709-1722. doi:10.1001/jama.2024.15815.

Mohamed:

Hey folks, and welcome to another great episode of Emerge and EM discussing another great paper. And this time I'm joined by my partner in crime and my amazing Canadian citizen, dr. Addy. Welcome back again to the show. And thank you for bringing up this paper to our attention. And I think our viewers would appreciate our insights about this paper. First of all, let's make it happen pun intended. So the name of the trial is the HAPPEN trial, and this was published in JAMA. I think that was September, 2024. And the study specifically talks about non-invasive positive pressure ventilation. And I know we have a lot of EMS audience as well as another audience from nursing physician assistants. So we need first to clarify some terminology. So Addy, can you tell us more about what actually non-invasive ventilation mean?

Addy:

Thanks, Mo. I mean, just to start off with, this is something that I nerd out about a little too much. So you're going to have to cut me off. Otherwise, this is going to turn into a two hour long podcast. so let me first explain this whole concept of noninvasive positive pressure ventilation. And I'm really sorry to my pulmonary critical care, Archie colleagues who are going to say, wow, that was a very simplistic explanation, but it's basically a Positive airway pressure is the best way to think about it. So whether it be CPAP or BiPAP, and we'll explain the difference in a little bit, the whole purpose is you're providing a constant amount of pressure by the system. The system is going to deliver a constant amount of pressure at all times. This is also known as your EPAP or your expiratory positive airway pressure. So even at the end of expiration, a certain amount of pressure in the lungs that's delivered by the system will stent those airways open. On top of that, there is an IPAP or an inspired positive airway pressure. And that's the amount of pressure delivered by the machine when the patient triggers a breath. In doing so, when a patient gets ready to exhale after inhaling. There's a difference between these two pressures. And if we can remember back to our early horrible days of physics and chemistry, when there is a difference between two pressures, that ideally means that we're moving along a pressure gradient. So we're able to assist the patient with breathing out. and thereby ideally improving gas exchange and assisting with gas exchange. So to put it another way, by having IPAP or by having an inspired positive airway pressure, we're allowing patients to breathe in more air and therefore breathe out more air along a gradient.

Mohamed:

So the majority of our patients who benefit from this is what? So COPD exacerbation, right? Maybe asthma exacerbation as we bridge them to other therapies. CHF exacerbation as well. What About. In the pre-hospital setting, they have CPAP only, that CPAP starts at a pressure normal, like 15 or 20. So when they come to you, to the ed, why do we need to change them to A BiPAP? I guess my question is, is it better to have a BiPAP versus CPAP or is the same?

Addy:

That's a really good question. So, There's actually two aspects of this. One aspect of it is that it depends on what is the underlying issue. Is it the issue with pure oxygenation, meaning for whatever reason, there's, for lack of a better word, there's crud within the alveoli that's preventing the alveoli from opening up and allowing oxygen to get in, or is an issue with ventilation, meaning an issue with inhalation and exhalation. The one aspect of it is that we don't know. A lot of the times that these patients are seen by EMS, EMS is also scratching their heads, like we're not too sure why they're in respiratory distress and CPAP works beautifully to bridge them. When they come to the ER, we're also scratching our heads and we're like, I don't know, some sort of respiratory issue is there. So we put them on BiPAP until we know what the issue is. I think the other aspect of it is we actually have studies that have proven that even if it is a pure oxygenation issue, like The greatest example is pulmonary edema, like flash pulmonary edema from CHF. We have studies that have actually shown that the administration of BPAP or bilevel positive airway pressure, really allows to ensure that we're staving off intubation just by assisting their ventilation.

Mohamed:

Okay, so your patient with COPD exacerbation comes into your ed. CPAP already applied by EMS. You look at them, they're in obvious distress. you're like, man, maybe some intubation in the near future. So ideally we want to prevent that. And, and first of all, I think we just, our audience need to know. Why don't we like intubation? Because my teaching back in residency was that if I even questioned the idea of intubation, I should just do it. Like it's, that means it does do it because that means that patient needs that intubation. But as I'm getting more and more experience in my attending life and seeing more patients and the complications sequelae they have in the ICU. pause more now before intubating my patients and see maybe tweak some things on that ventilator at bedside that BPAP see what I can do to maximize oxygenation and ventilation before intubating them. And this is what the study is all about. Like how can we, you and I as clinicians prevent intubation, right? So intubation is associated with infection, VAP or ventilator associated pneumonia, myopathy, prolonged ICU stay and all the complications that you and I very aware of. In addition to that, intubation is not a benign procedure, right? it's associated with complications. If we don't do it maybe in the right way or if we are not prepared enough for that intubation because peri-intubation cardiac arrest can be avoided with preparation. Going back to the HAPPEN trial, study specifically looked at high intensity non-invasive positive pressure ventilation versus low intensity ventilation in patients with acute COPD exacerbation and persistent hypercapnia. I know I have a lot of issues with this study, but first, let me get your input. Maybe provide us with the background of the HAPPEN trial.

Addy:

yeah, before I even get to the background of the trial itself, just to explain some terminology for all our folks out there. So high intensity, noninvasive positive pressure ventilation basically means that you're increasing that IPAP or that inspiratory pressure in such a way that you're aiming for a higher tidal volume of about 10-15 cc per kilogram versus low intensity, which means you're adjusting the IPAP more to aim for a tidal volume closer to 6 to 10 cc's per kilogram. Then going on to the trial itself. So this trial was performed in non ICU, respiratory wards in China. enrolled about 300 patients and basically the patients needed to have hypercapnia. So a partial pressure of CO2 greater than 45 millimeters per mercury. And they were randomized after receiving six hours of low intensity non-invasive to either getting low intensity versus high intensity. And the results were interesting. they were basically looking to see what, whether the primary outcome of patients that have high intensity non-invasive Will they actually be able to reduce the need for intubation? Will that high intensity positive pressure reduce your intubation rates? the results were that patients in the high intensity group were significantly less likely to meet intubation criteria. So that was about 4. 8 percent versus the low intensity group, which is about 13. 7%. However, the actual intubation rates, when you look at the study a little bit more closely, were actually closer to 3. 4%. For the high intensity group and 3. 9 percent for the low intensity group. So not a crazy difference.

Mohamed:

Okay. Addy, I have a lot of questions about this. First of all, why these patients are not in the ICU? Number one, because and I know like if anybody who needs a mask on their face and presents with COPD exacerbation, they normally go to the ICU. Yeah. Yeah. The other question, I have a couple other questions and I don't mean to interrupt you. Is first of all, these patients already put or placed on kind of low intensity inspiratory pressure at, you know, for six hours before random randomization. Is that, is that correct?

Addy:

yeah, that's what I understand from the paper,

Mohamed:

So let me ask you this, Addy, how many of your patients with COPD exacerbation who needed noninvasive to stay in the ED for more than six hours.

Addy:

I would like to say that the answer is most of them are not staying in the ER for that long. But as we know, it's that time of year, respiratory seasons on the rise. We're getting more and more patients that are just stuck down there in the ER that we have to actively manage. So I don't think that this is not relevant to us as a result, it really doesn't beg the question from a systemic point of view, can we just ship these patients on up, but think I simple now,

Mohamed:

I agree with you. And I know you and I were dealing with this on a daily basis, but at the same time, they already placed these patients on low intensity

Addy:

right.

Mohamed:

ventilation. That's one issue for me. The other issue is that their definition of a sick COPD exacerbation patient is vastly different that what you and I consider a really bad sick patients. So for example, a lot of these patients were able to talk to you had relatively speaking, pretty good gases, you know? So when they came to their hospital system they were placed on non-invasive ventilation. I looked at their numbers. They were not that impressive. would not care about that obtunded patient. Mostly, that's one spectrum or the other spectrum that still awake patient with severe bronchospastic disease that we're trying to, you know, maximize therapy or bridge them to therapy with noninvasive ventilation. So again, the patient population that you and I treat in the ED or even in the ICU is very different than their patient population. So probably something I know we're going to discuss the limitations. But just something to tell our listeners to always be critical when you read a paper and before you jump into conclusions based on reading an abstract, read the details of that study. Does that patient population apply to your setting? That's one. And then number two is, Is that going to change my practice, which you and I will be discussing. So that's what I want to put out first. Again, I'm going to digress and you already know my opinion about this study.

Addy:

No, absolutely. No, and it's a really good point that one, this paper has a lot of flaws and I am not saying that it is the Bible when it comes to noninvasive what I like about this paper, though, is it gives me the excuse, first of all, to hang out with you, which is always fun, but also just gives the excuse to talk about noninvasive and how important and beneficial it is. just to start off with, giving credit where credit is due, high intensity, noninvasive, positive pressure ventilation prevent clinical deterioration. I think the study does help to at least show some sort of correlation between that because fewer patients in that group met the predefined criteria. And when they calculated it out in this paper, I think the number needed to treat was about 11 for high intensity pressure. That's meaningful, but the interesting thing about this paper in particular is many patients that were in the low intensity group crossed over into the high intensity group, most of them were stabilized without needing intubation.

Mohamed:

So the patients who would otherwise have been intubated, were not intubated because of the high intensity inspiratory pressure. Is that correct?

Addy:

That's essentially what has been reported. It's just, it's impossible for us to tell if this was truly statistically significant or not.

Mohamed:

Okay. Let's get back to the prehospital setting and the ED setting that you and I work. I'll give you a case. Okay. a 53 year old male with COPD exacerbation, daily tobacco user missed a doctor's appointment, severe shortness of breath, hypoxic in the 70s, maintaining mental state so far by EMS EMS tried inhaler therapy after initial examination showed. wheezing bilaterally. No stigma of CHF was having a little bit of cold recently. That's what he thought that it triggered his symptoms. So the CPAP, they started the CPAP prehospitally at 10, then the patient was still having shortness of breath, was getting more anxious. So by the time they got to the ED to you, they were still very, you know, tremulous and clearly they're hypoxic sats anywhere between 89 to 90%. On that CPAP. So based on this study, what are some of the things you will be changing in your practice, if anything at all?

Addy:

I want to empower them because, you One big aspect of it is, if you have obstructive lung disease, your airways are going to be very tight and very closed off. At least with CPAP, you're opening up those airways, you're stenting open those airways just enough so that even though we're not able to get the best sort of ventilation possible, it will still help with gas exchange. So just to empower thank you so much to our EMS colleagues that recognize respiratory distress, put them on CPAP and bring them in. And in terms of what I would do and what, I would not so much change because of the study, but empower myself more because the study is when I put them on that BiPAP or that bi level positive airway pressure, am going to be a little bit more aggressive. I think the standard thing that we're talking residency is set it and forget it. 10 over 5. 10 meaning the I PAP, 5 meaning the E PAP, and then just walk away and see my ankle sprain down the hall. Instead, what I'm going to do is, 1, I'm probably going to start a bit higher. I'm going to aim for maybe 15 over 5, 20 over 5, something with a higher delta, meaning a higher difference between the I and the E. by doing so, I allow for that greater pressure gradient. And the 2nd thing I'm going to do is I'm going to stay in that room, and I want to take a look at what tidal volume is showing up on the BiPAP. And maybe we can link a little picture in the show notes afterwards. But if we're able to take a look on that, sorry, and take a look and see what exactly is the tidal volume that presents, we can figure out our interventions working. If, say, for example, the tidal volume is reading 300 to 400 in a normal size adult above 5 feet in height with a normal weight, that's not good enough. I'm ideally aiming for 600, 700, 800, something higher that really indicates that they are having very good gas exchange. And what I would do is I would be aggressive. Maybe I would walk out of the room, get a gas. If there's no improvement with that gas, I might even jack up that IPAP a little bit higher to the biggest takeaway or the biggest point I want to try to make is 1. This is not a set it and forget it. Static process, but 2, this is a very dynamic process that we need to be actually in the room, helping out to try to titrate appropriately. Obviously before all of this, I will bow and apologize to the RT directly for touching the machine without their permission, but I think they also would agree that this would be so helpful to have that open discourse between the two of us.

Mohamed:

I feel like I need to summarize. So that patient comes into you, you go high on the inspiratory pressure. So you go to, instead of the 10, maybe to 20, 20 over five. Now they're on a BiPAP. and I mean, in this study, they went to as high as 30 or not right? Which brings up another question in my mind, right? And you, you spoke about those discussions with respiratory therapist. So, if I was the respiratory therapist and I'm like, Hey, you crazy Canadian doctor, what are you doing? Because increased inspiratory pressure is gonna cause this patient to have lots of air in their stomach. They're gonna vomit. They, they are going to have all these complications. So is there really a risk of aspiration? Is there a risk of stomach insufflation with increased pressure? So what are some of the complication of the high intensity approach?

Addy:

Absolutely. I think that's actually one of the biggest complications that can arise is gastric distension that occurs from too much air just going down the esophagus into the stomach. On top of that, yes, as a result, if there's too much air in the stomach, there is this feeling of I need to vomit and patients have vomited before from being on higher pressures like this. Another complication, unfortunately, is the. The more like psychological impact, a lot of these patients, they, I don't want to use, go so far as to say the word traumatized, but they really do feel the sense of anxiety that occurs. And it can actually detriment them because the next time they go on BiPAP, they may have that same sort of feeling of, Oh my God, last time I was on this, I was very unwell. I felt like I wanted to throw up. I was very sick, very anxious. And I guess the question posing it back to you is, Are those risks worth the benefits of not intubating the patient? And I think it really is a balancing game. I don't think there is a right answer.

Mohamed:

And I would tell you, it depends, right? Because if my patient is already obtunded, I would you probably be extra cautious with those inspiratory pressures? Maybe. 15, you know, over five, go to, go to 20 then kind of keep, like you said, keep reassessing them, stay at bedside, see if there is any improvement in the mental state. If they're already awake and clearly bronchospastic, then obviously I'm already aggressive with my other therapies. with the bronchodilator, the steroids, magnesium, even epi and maybe I would go to 20, inspiratory pressure on those patients. The obtunded ones that I'm, they're already a risk of aspiration. I tend to be maybe extra cautious. That's kind of my approach at it.

Addy:

And I 100 percent agree with that approach. I really don't think that this is a one size fits all. And you have to be, you have to be that intrepid clinician that balances the risks and benefits, and actually adding on to all that you're saying, the making sure that you're really dialing in your obstructive lung therapies, making sure that you're really like taking a look at this patient appropriately, getting your chest x ray, et cetera. Don't forget your low tech stuff as well. Really make sure you set up that patient fully to ensure that their lungs open up, that their diaphragm has the ability to actually open up appropriately, wake them up, be a little bit unkind in the sense that they may want to be sleepy. Nope. You shake them awake and you're like, sorry, ma'am or madam or You cannot sleep throughout this entire process. Ensure that there's a good feel around the mask. I have so many patients that for whatever reason, if they have a beard or they have a, a strange sort of asymmetry to their face, they can actually detriment the seal that we have around the mask. And therefore, you're not actually getting that pressure into the air areas. But instead, you're providing BiPAP to the surrounding room in the er, and then also make sure that the tube isn't kinked.

Mohamed:

And again, just to be clear with the results of this paper, the HAPPEN trial is that there was no difference in intubation rates between the low intensity and the high intensity strategy because of that crossover. just want to be clear with that. It's just we have avoided those who would intubated from getting intubated and that's the gist of the paper. I agree with you. I feel like I'm now probably going to be a little bit more aggressive with the inspiratory pressure initially. If my patient is clearly a bronchospastic and maybe slowly up titrate that and make sure that the patient is frequently reassessed too. Another thing that I feel it was a big mistake in this study, or maybe not the best goal, is the investigators tried to normalize pH in these patients normalize their CO2. Dude, you and I, walking, breathing, I don't want you to have my CO2 at baseline. My COPD patients, they're chronically hypercapnic and I don't want them to go back to 35, 45 CO2 numbers. So again, that's like an unrealistic goal in my opinion maybe my goal is to kind of normalize that bicarb or get them back to their baseline CO2 without needing to kind of completely normalizing it. That's not our goal. Do you have anything to add about this?

Addy:

I think I think the only thing that I would add to that is this paper used numbers and humans are not numbers. I would say, and I would urge, like, all of my colleagues or critical care colleagues, all my colleagues out there that instead of looking at the numbers and checking a gas every 30, 40 minutes, you're just going to stress yourself out. Look at the patient. Talk to the patient look to see if they're breathing improving. Do they look like they're breathing with a better ratio of inspiration to expiration? Do they look like they're improving? Are they meditating much better? That's more important than looking at some gas level because yeah, this is how we can actually help our patients better. If we look at the gas numbers and we try to overcorrect or undercorrect or whatever, I think we complicate the issue way too much. So I totally agree with you, Mo. No, I do not want my COPDer to be having a PCO2 of 30 because I feel like that would make everything much worse.

Mohamed:

This is a common clinical theme and Pearl, because I feel like a lot of clinicians out there, they focus on a number one, a monitor. This should not be our goal. Our goal is to look at the patient in front of us. continue reassessing. I know that's sometimes hard as our departments get busy. We see a lot of patients, but we have to pay extra attention to those sick ones because they deserve the best care. Can you summarize some of the main takeaways from this paper?

Addy:

Absolutely. So the main takeaways in general is number one, be more aggressive. With both CPAP as well as BiPAP. So if you're in the EMS world, CPAP, if you're in our world, the BiPAP be more aggressive with initiating it. Number two, that tidal volume is key and the best way to increase tidal volume and to improve gas exchange is by being aggressive with increasing your IPAP or the inspiration pressure. finally. Don't forget your other low tech methods of improving gas exchange. These are human beings in front of you, not numbers. So set them up fully, ensure they're fully awake, ensure there's an adequate seal around the mask, and that there's no kinking of the tubes that connect from the mask to the machine.

Mohamed:

And then don't forget your adjuncts, you know, the beta agonist, the steroids maybe magnesium, epinephrine, all these things are happening at the same time as they are being support from a ventilatory standpoint. Thank you so much, Addy. I really enjoyed this discussion and I look forward to discussing the next paper with you. So I appreciate you for being here.

Addy:

as usual, this is always fun. Thanks, Mo.