Hi guys, can we like move in, like all like really far back? Thanks guys for joining us today for our session on cystic fibrosis in the ICU. We can figure out how this works maybe. There we go. So first off we have Dr. T, she's gonna be talking about antimicrobial drug selection for acute pulmonary exacerbations. Hopefully y'all can hear me. Apparently no one can see me above the podium. So I will stand away from that. Okay, so I'm gonna talk about antimicrobial drug selection. I'm the adult director at UT Health in San Antonio. So for objectives, I think, you know, before we talk about antimicrobials, we really have to talk about what an acute pulmonary exacerbation is, and then review the treatments for that, then discuss antimicrobials, and then review non-antimicrobial treatment for pulmonary exacerbations. So we'll start off with a case. This is a real case that I took care of recently. So we have a 39-year-old woman who comes in with moderate pulmonary disease. Her baseline FEV1 is around 65%. She has pancreatic insufficiency, chronic rhinitis sinusitis, and then GERD. So she comes to the ER. She has shortness of breath, increased cough with green sputum production, fever, and body aches. Her oxygen stat on arrival is 86% on room air, and then she was placed on three liters of oxygen. Of course, anybody who comes into the ER with any sort of fever or shortness of breath, they get a COVID test. So she's negative for COVID, but she does test positive for influenza A, and then this is her X-ray shown here, which you kind of see there's some lower field infiltrates, and then some bronchiectasis pretty diffusely throughout. So then she gets admitted, and then we do spirometry on her. And as you can see, her FEV1 is showing predicted 37%, and her baseline is around 65. So at this point, we would call her an acute pulmonary exacerbation. So what that looks like is that there's usually a progressive decline of lung function and acute worsening of respiratory symptoms, usually from baseline. There's actually not a consensus definition for an acute exacerbation, but some clinical features would be increased cough, sputum production, shortness of breath, chest pain, loss of appetite, and or weight loss. So how many patients have pulmonary exacerbations? So this is kind of a really cool schematic looking at patients from birth to 18 years and over, since we mostly treat adults. I'll look at the dark blue line here. And so starting from 2006 up until kind of now-ish, about roughly almost half the patients have exacerbations, but 2020 is kind of an anomaly because Trikafta came out in 2019, and then the pandemic happened, so a lot of patients actually quarantined, and so there was less viral illnesses overall. So the number really dropped, which is pretty impressive. So why do we care about pulmonary exacerbations? So it really shows different outcomes, and so the number of exacerbations, if that increases, then it really decreases survival. And I feel like these Kappa-Meier curves are pretty drastic. So even looking at patients who've had one to two, or less than one or two exacerbations, their survival decreases dramatically. And then it depends on, actually, if it's severe enough to need IV antibiotics as well. And so if they do need antibiotics for their exacerbation, then their survival also decreases. So what causes exacerbations in these patients? So it's really complex. There's a relationship between the host defense and then airway microbiology, which then really impacts how much sputum they're producing, and then the airflow obstruction. So the etiologies that we commonly think about are viral infections. Those can be independent of bacterial infections, or can trigger bacterial infections, and then acquisition of new organisms. But more commonly, it's actually a change in the bacterial density of colonizing flora. Looking at the infections that most commonly the CF patients have. So when they're younger, they mostly predominate is gonna be H influenza and staph. And then when you get older, that's when pseudomonas and multi-drug-resistant organisms start coming about, like MRSA. And so these are the things that we would target for patients with exacerbations. So continuing this case. So the patient was admitted, and initially they're like, well, maybe all of her symptoms are due to flu. So she got started on Tamiflu. And then after five days of therapy, she doesn't really feel better. Her PFTs were repeated, and there's no improvement in her FV1. And then, so this is what she grows. She has pseudomonas, and as you can see, there's lots of resistance. So you're trying to decide what to put her on. And she has history of ototoxicity and vestibular dysfunction with aminoglycosides, history with tobramycin. And then she says she has some throat swelling that happens with Zosyn. And in the past, she was treated with ceftazidime and ab-bactam in the past. So how do you decide what antibiotics to try? So every time we talk to ID and things, they're like, what are you doing? But so for antibiotics, you really have to select it based on patient tolerance, allergy profile, and pyroculture data. And then resistance is actually not an agent that's contraindicated for use, and I'll talk about that in a little bit. And then treatment changes should be done based on the clinical response of the patient. And since we talked about how when they get older, these patients end up growing a lot of pseudomonas, so that's what we usually will target the most. And standard pseudomonas treatment's gonna consist of two antipsuedomal drugs. There's actually no data supporting that, but that's what we do. And then there's no evidence to support the use of inhaled antibiotics in addition, because that increases systemic toxicity. And then if you think about it, when they're having an exacerbation, they have lots of mucus plugs and impactions, and so that the inhaled antibiotics may not go into the lower airways, and maybe just treat the upper airways, and so they may not be effective. And so for example, this would be kind of a choice that you would use would be immunoglycoside, which is like tobramycin, and then a beta-lactam being cefepim or zoosin, but that also kind of depends on patient allergy and tolerance. So when we look at dosing for these antibiotics, it is quite different from traditional dosing too. So they looked at once daily dosing of immunoglycosides versus the traditional three times a day dosing, and they showed that once daily dosing actually reduces the risk for systemic toxicity and side effects. So for example, we'll do tobramycin 10 mg per kg every day, and then we'll check for blood peak levels 25 to 35 with an undetectable trough. And then looking at the other antibiotics, there's really insufficient evidence to recommend continuous infusion of beta-lactams, so you can do intermittent dosing if needed. And then there's lots of side effects with these antibiotics including nephrotoxicity, ototoxicity, and vestibular toxicity, which may not be reversible in these patients, so it's really important to screen these patients and look at their labs every day. So this is what kind of drives ID a little crazy is that there's really poor correlation between in vitro susceptibility data and clinical outcome with these patients who are chronically infected. So things that are postulated is that the expectorated isolates may not be representative of the entire CF lung because it depends on kind of where they're at and their exacerbations and what sputum you're able to collect, or if they're not coughing up at all, you end up doing a throat swab. And then not all bacteria isolates tested contribute to clinical disease, so they grow up multiple different species of pseudomonas, for example, and that may be not the pathologic one that's causing disease. I really like this schematic. So this kind of looks at the bacteria isolate that you have, and there's so many confounding factors for clinical response, including patient age, their stage of lung disease, which they've kind of looked at these patients who have more severe disease, and so they've been exposed to more and more antibiotics, so they have more resistance patterns, and they most likely have a predominant organism rather than younger patients who kind of have multifloral disease. And then looking at their different phenotypes as we kind of talked about this morning about different classes of mutations, and then kind of what's in their community, and then past history of antimicrobial treatment. So for duration of therapy, there's really insufficient data for an optimal duration, but usually we treat patients until their symptoms resolve and their lung function recovers. The length of antibiotic therapy is usually 10 to 14 days. I know in the UK, they'd say at least 10 days. And then this looks at, this picture looks at kind of the median of the duration of antibiotics. So for patients 18 over, the median's around 13 days, and then they're usually hospitalized for about eight days. And then in kids, roughly the same, but they're hospitalized for a little bit longer, because we can probably do IV antibiotics at home for adults. So looking at duration of antibiotics, this is the only and largest randomized control to look at pulmonary exacerbations in CF. So what they did is that they enrolled patients and then had their first visit looking at their FEV1. These patients were having exacerbations, and then they would treat them with standardized antibiotics and then they'll look at seven to 10 days after antibiotics were treated or used. And then as you can see, like in that left graph, their PFTs kind of went up. They then put them into an early response group or a non-early response group. So the early response group had improvements in their symptom scores, and then FEV1 increased about 8%. And then they randomized those to 10 to 14 days. And then for the non-responders, they put them into 14 or 21 days. As you can see, there's not much of a difference when they looked at visit three, which was about two weeks after antibiotics were completed. And then they looked at the time to their next exacerbation between the early responders and the non-early responders. And that didn't really show a difference either. And then the median time to their next response was about six months or so. And so I think more to come for this study. And so maybe the durations should be shorter for certain patients. But I think it's super variable what kind of different clinics practice. And so it would be helpful to have some more standardized care for these patients. And so I think antibiotics and all that stuff is really, really important. But you need to really do adjunctive therapy. So airway clearance and pulmonary therapies are really important for everything to kind of clean out the lungs. And so the airway clearance therapy should be intensified. So it's increased time and frequency for all treatments. And then suggested therapies would be a bronchodilator to open up their airways. And then a mecolytic to thin out their airways, make it easier to come out. And then airway clearance therapy, like vest therapy or IPV, things like that. So in summary, acute pulmonary exacerbations decrease survival. The antibiotics are selected not based on susceptibilities, but patient tolerance, allergy profile, and prior culture data. There's not an optimal duration, but kind of more studies are coming from that. And then antimicrobial susceptibility testing is not really predictive of treatment response. And then acute pulmonary exacerbations should involve more than antimicrobial administration. So airway clearance, nutritional support, and psychosocial support. Okay, thank you. Thank you. All right. So for those of you who don't know me, I'm Gretchen Winter at the University of Alabama at Birmingham. And I'm gonna be talking about mechanical ventilation and ECMO in patients with CF. So we will start off, I have nothing to disclose with our objectives. And basically we're gonna talk about varying levels of respiratory support for these patients in the ICU. So a little bit of background information. Advanced cystic fibrosis lung disease is very common. And it is unfortunately, respiratory failure from this is the most frequent cause of death in patients with cystic fibrosis. Now the CF Foundation patient registry shows that 18% of patients who are older than 30 and 25% of patients who are older than 45 actually have an FEV1 of less than 40% predicted, which is not good. So while outcomes are improving for these patients with advanced cystic fibrosis lung disease, they're still in an approximately 10% risk of death per year for these patients who have an FEV1 of less than 30%. And the majority of hospitalizations in patients with CF are for respiratory related complaints. And they account for 89% of those admissions in the US according to a 2013 study of the National Inpatient Sample Database. Additionally, in another analysis of CF admissions, 13% of the hospitalized patients with CF did require ICU level of care. And 17% of those patients actually needed invasive mechanical ventilation. So when it comes to treating these acute CF exacerbations, as she just talked about, really your tenants of therapy are supplementation of oxygenation and ventilation as necessary, airway clearance, antimicrobial therapy, and then nutritional support. So let's start off by talking about those different types of respiratory support. So just as in other pulmonary disorders, the level of respiratory support in patients with CF should be tailored to that patient's specific respiratory insufficiency, their work of breathing, their levels of hypoxia and hypercarbia. Now heated, humidified, high flow nasal cannula, and man, that's a tongue twister, has a number of potentially beneficial physiologic effects. It can reduce your nasopharyngeal resistance, it can lead to washout of the pharyngeal dead space, it can generate peep, and it can help in alveolar recruitment. And in turn, that reduces your inspiratory effort and it improves your lung compliance. Additionally, it can allow for oral intake, which helps to improve nutrition, which is very important in these CF patients, and it can allow for better expectoration and airway clearance, which is also exceptionally important in these patients. So the basic takeaway from this slide is that high flow nasal cannula can be considered and useful for patients with CF who have hypoxia or increased work of breathing, but who do not require invasive mechanical ventilation and who do not have acute hypercarbia. So let's talk about non-invasive ventilation or BiPAP machines then. So there are no prospective studies that validate the use of non-invasive ventilation for acute respiratory failure in patients with CF. But there were favorable outcomes in a small retrospective study done by Sprague and colleagues and those showed decreased respiratory rate, increased oxygenation, decreased FiO2 requirements, decreased transcutaneous carbon dioxide levels, and improved atelectasis. So what we do know from studies is that non-invasive ventilation may improve gas exchange and it may help with sputum clearance, but we don't really know the impact on acute exacerbations or disease progression in these patients. So this retrospective study by Katergi looked at non-invasive ventilation as the first step in management for acute hypoxic respiratory failure in 16 patients with cystic fibrosis in an ICU. Now the mean duration of time on non-invasive ventilation was 10 days, which is a lot of time to spend on an IV. Half of these patients did die and those patients were intubated due to failure of non-invasive ventilation. But the 50% of patients who survived without being intubated were discharged home with long-term ventilation as necessary until they received lung transplants. So they concluded that non-invasive ventilation may be considered for patients with CF who are admitted to the ICU with respiratory failure and that we should also consider long-term non-invasive ventilation nocturnally for patients with chronic hypercarbia to help keep them stable while awaiting lung transplantation. Now a couple of caveats to this. We should not use, just as with any other patient, non-invasive ventilation for people with severe respiratory acidosis or who are abdundant. We wanna initiate this early in the course. If you wait too long, you gotta go straight to the invasive. And then to optimize success, we also wanna make sure that we're monitoring then their gases and their work of breathing and mental status very closely. So what about the dreaded invasive mechanical ventilation? So this has been really controversial for a long time in patients with cystic fibrosis in terms of intubating for acute on chronic respiratory failure. Now intubation has often been advocated for and viewed as appropriate for patients with CF who have reversible causes of respiratory failure like hemoptysis or pneumothorax. But historically, there have been very poor outcomes for patients with acute on chronic respiratory failure that were managed with invasive mechanical ventilation. Studies have been limited, but they have mortality rates ranging from 45 to 75% depending on the group studied. Now, Outen colleagues looked at the Texas Inpatient Public Use Data File, and they looked at patients with CF and ICU admissions between 2004 and 2013. What they found is over that time period, the rates of the use of invasive mechanical ventilation actually increased only at 11.5% in 2004, all the way up to 19.2% towards the end. They also found that short-term mortality with invasive mechanical ventilation was only 41.8%, and that over 60% of survivors were actually discharged home instead of SNFs, LTACs, et cetera. So the incomparable Dr. Dazenbrook, who we'll be talking next, and his colleagues also used the Nationwide Inpatient Sample Database, and they evaluated in-hospital mortality in patients with cystic fibrosis and invasive mechanical ventilation. And they looked from 2002 to 2014. Now this study, unlike the prior ones which were looking at 14 patients, 30 patients, looked at over 1,700 adult patients with CF who underwent invasive mechanical ventilation. And they found only that there was a mortality rate of only 44.5%, which is huge, but it's a lot better than 75. They also found that over time, the proportion of patients who survived the invasive mechanical ventilations did improve, likely due to our improvements in protocols. They found that most of the survivors were discharged home or home with healthcare, with smaller proportions being discharged to short-term hospitals, skilled nursing facilities, et cetera. And factors they identified that were associated with increased mortality included female sex, acute renal failure, malnutrition, and older age, keeping in mind that older age is 25 to 32, which, man, does that hurt. So, what about sedation and analgesia? When it really comes down to it, your overall goals for sedation are the same as for patients without CF. And your same best practices should be followed. That includes daily interruptions of sedation, maintenance of light sedation with validated scores, early and aggressive mobilization, appropriate weaning protocols, all the same stuff. But there are a couple of unique factors to consider in patients with CF. First, you may require higher doses of these sedatives to achieve your goal level of sedation, which is likely due to alterations in metabolism. Second, you want, whenever possible, to avoid high-dose narcotic infusions, as that can precipitate a bowel obstruction by distal intestinal obstructive syndrome, or DIOS. And if you have a patient on any kind of sedation, you wanna make sure they have a very aggressive bowel regimen and that you are monitoring them and their bowel movements really, really well. This isn't someone that you can let go of two days without pooping. So what about the all-elusive ECMO? So there's been really inconclusive data regarding the survival benefit for patients with generalized ARDS who receive ECMO versus those who just get mechanical ventilation alone. Now, some potential advantages of ECMO over venting alone include less sedation, you can ambulate more, and for patients with CF, they can participate more in airway clearance. Now, there was this single center study done by Biscotti, and that sounds tasty, and that included 27 patients with CF, and they looked at patients with respiratory failure and found that there was a 67% survival when they were supported with ECMO in addition to mechanical ventilation versus only 51% survival in patients who underwent ECMO for other causes. So basically, they found that the patients with CF who got ECMO actually had better outcomes than general people who got ECMO. And then Hayes and colleagues did a retrospective study of 73 patients in the Extracorporeal Life Support Organization Registry, and they found that the hospital survival of cystic fibrosis patients who received ECMO was 52%, which is not shabby. So, let's see, oh. Okay, so this retrospective study looked at the demographic, disease-related, and ICU-related factors in 52 critically ill patients with CF and respiratory failure who were treated with either mechanical ventilation alone or mechanical ventilation with ECMO. 52% got mechanical ventilation alone, and 48% also got ECMO. Now, 75% of the patients in the vent-only group and 100% of the patients in the ECMO group were listed for lung transplantation. Now, reasons why some of the ones in the vent-only group were ineligible included patient preference, growth of Burkholderia sinensis patia, a patient with HIV, anoxic encephalopathy, and a patient with poor adherence and malnutrition. And of note, none of these patients in the study were on CFTR modulators, so this was pre the developments that we now are seeing the effects of. So, what they found is for the patients in the vent-only group, they spent a mean of 10.6 days on the ventilator, and for patients who also received ECMO, they spent a mean of 15 days on ECMO prior to receiving transplant. Now, the ICU length of stay was longer for patients on ECMO, as was the total hospital length of stay, but you could argue that those who were transitioned to ECMO had more severe disease, and thus that would be predictable. Now, 33% of the patients in the vent group and 62% of those in the ECMO group did undergo lung transplantation during that same admission. So, when you look at the patients in the vent-only group, seven of them were ineligible for transplant. Four of those survived a discharge, and three died in the ICU. So, over half of the ones who were ineligible for transplant and on event still went home. Now, of the 21 patients in the vent-only group who were listed for transplant, two-thirds of those survived a discharge, and half of those had undergone transplant. And then, of those seven patients who did die who were eligible for transplant, those patients were not transitioned to ECMO for a variety of reasons, including anoxic encephalopathy, liver failure, and septic shock. So, for the patients, though, who did survive their ICU admission, regardless of their group, there was no statistical difference in the number of patients who were discharged home between either of those groups. And the overall mortality was 37%, not bad, with no statistically significant difference between those groups. And all deaths were in patients who did not receive a transplant. So, these results actually show significantly better survival than in prior studies, and that's thought to be due to advances in both CF as well as advances in ICU protocols over time. So, currently, ECMO is generally reserved for patients who are candidates for lung transplant, but I would argue that there may be other cases when it could even be considered reasonable, especially for patients with only mild to moderate lung disease who have another kind of reversible process that needs support. Now, a couple of quick points on similar topics. First of all, if you look at the CF Foundation guidelines for referral for transplant, I won't make you memorize all of them, but there's a little caveat at the bottom that says that any patient who has two or more exacerbations requiring inpatient hospitalization, or one exacerbation requiring positive pressure ventilation should be referred for lung transplant. So, any of these patients that we're talking about on any form of positive pressure ventilation should be getting a lung transplant referral, so keep that in mind. And then, since we're talking about these topics, we should also broach on palliative care. Of note, palliative care concerns are really underestimated in patients with chronic lung disease in general and in CF, and individuals with CF and their caregivers report that they are both willing to discuss these things earlier and that they want to discuss these things earlier. Despite these things, and the data suggesting it, most of these advanced care planning discussions tend to occur during acute illness and near the end of life, unfortunately. And another thing to keep in mind is that advanced care planning and palliative care discussions and aggressive treatments are not mutually exclusive, and that these palliative care and ACP discussions should be occurring prior to, and even concurrently, with lung transplant evaluation. So, our take-home points. Consider high-flow nasal cannula for patients who have increased work of breathing or hypoxia, but without acute hypercarbia. Consider non-invasive ventilation early in the course for patients with acute hypercapnia, watch their mental status, and consider long-term non-invasive nocturnal use for patients with chronic hypercarbia. You can consider invasive mechanical ventilation for patients with progressive respiratory failure. It's not as bad as we once thought it was. You should minimize narcotic infusions for your patients on sedation. Consider ECMO for eligible patients, especially those who may be eligible for transplant. Consider a transplant evaluation for all patients in the ICU who require positive pressure ventilation, and advanced care planning needs to be initiated early. I have here a number of references for your perusal, which I'm happy to send out if you'd like to see them in more detail, and thank you so much. So, we'll... Oh. Thank you, thank you. So, next we have Dr. Elliot Dazenbrook, whose study I referenced earlier. He'll be coming up to talk about hemoptysis and cystic fibrosis. Thank you. All right, thank you very much. So, we'll be talking about life-threatening hemoptysis and cystic fibrosis today, and this is really gonna be from the perspective of the CF physician, okay? So, most of us that are pulmonologists are also ICU doctors. I see a lot more massive hemoptysis in my non-CF patients than I do in my CF patients, but like I said, this'll kind of be from the perspective, what do I think about when it is the CF patient, whether or not I'm actually working in the ICU? So, this won't be a primer on the treatment of massive hemoptysis in general. No disclosures for this specific talk. So, at the end of this talk, I hope you come away with a couple of things. Number one, tranexamic acid. You should be using this in your outpatient clinic. You should consider using this as a nebulized formulation during inpatient stays for patients with mild or moderate hemoptysis to prevent them from progressing to massive hemoptysis, right, so sometimes massive hemoptysis is just, you know, very sudden, but most of the time, that is not the experience in CF, and so you wanna become familiar with that. We do not perform bronchoscopy for massive hemoptysis in CF. This is very different than what we do for non-CF. We'll go through that. There's a high recurrence rate of hemoptysis in CF, so if someone undergoes bronchial artery embolization and they bleed again, that's not a failure. Often, IR gets very upset. People start talking about surgery immediately, but that is gonna be the expected course for most of our CF patients, so you have to be the voice of reason as the CF physician in the room, but that's not the end of the world, and then similar to what Dr. Winner just said, an episode of massive hemoptysis should trigger you to think about a lung transplant referral based on the most updated guidelines, so these are the types of things I'd like you to take home today and what we'll kind of cover as we'll talk throughout the next several minutes here, so massive hemoptysis in adults, this is data from the U.S. CF patient registry, and so with 2020, that's the most recent data that we have. 2021 data will be coming out in the next couple of weeks when we gather in Philadelphia, but there's been about a 50% drop in hemoptysis and massive hemoptysis in the U.S. Now, obviously, 2020 is confounded by COVID, but I think most of us believe that a large percentage of this is due to the impact of the modulators, the pathogenesis of massive hemoptysis and hemoptysis in general is going to be around airway inflammation and infection and that's significantly decreased since late 2019 with the widespread availability of the modulator. So before, you would see about 1% per year of massive hemoptysis. Now that's about one out of every 200 patients now. So if you have a center with 200 patients, you're going to probably see about one a year. So you still are unfortunately going to see this. So first in the last three to four years, there's been two papers, both published in chest that have really changed the way that I do my practice in terms of outpatient management of hemoptysis and the inpatient management of hemoptysis. The top one is from the Boston group, a very large pediatric and adult CF center. And then an RCT that was not CF specific, about a third of the patients were brachiectasis, but certainly I extrapolate that to my CF population. So in the Boston group, what they basically did is really created a process for using oral tranexamic acid. In the US, insurance coverage and cost is pretty reasonable. So that's the one that we go with. And we give these prescriptions to our patients. They have them on hand. We kind of give them instructions of when to take them. For our patients that kind of have this recurrent low level hemoptysis. And our nurses are very good with it. And it kind of gives the patient some comfort. They can take the pill and then call us and we can kind of triage from there. So I found that to be very helpful in our management of hemoptysis as an outpatient. And then the second study from Wand and colleagues, again, not CF. I included the flow from figure one because massive hemoptysis patients, which we're talking about today, was specifically excluded. But if you want to prevent the progression to massive hemoptysis, we use nebulized tranexamic acid when our patients get admitted for their hemoptysis. Specifically, again, if they have blood streaks, sputum, I'm not giving them nebulized tranexamic acid, but if they're having bright red blood that's kind of in that moderate to low level massive hemoptysis over 24 hours, then we're definitely using this. We met with our pharmacist and got it included in the formulary and kind of cleared through all of the hurdles before we had a patient that actually needed it. A lot of people have to sign off on it, who can actually give it, et cetera. So if you don't have that as part of your process, I encourage you to meet with one of your pharmacists that you have a relationship with and get this on your formulary. So the first thing, the big difference between CF and non-CF in terms of life-threatening hemoptysis is this issue with bronchoscopy. So a CF patient will be in the ICU, life-threatening hemoptysis, and IR gets the call, hey, we need an embolization. And they say, well, what did the bronch show? And then the ICU team is like, ah, we got to call bronch. We got to call the bronch team. We got to get down here. We got to do a bronch. And so your role as the CF physician is to say, hey, look, I'm willing to have a discussion about this just so you know the international guidelines for the management of hemoptysis in individuals with CF recommend against doing a bronchoscopy, and they actually call it inappropriate management. And so I say, hey, look, those are guidelines. It's expert opinion. I'm willing to have a conversation here. But really, our goal is to expedite embolization. So we don't want to waste time doing a bronchoscopy. Anyone that's done a bronchoscopy in a CF patient, there's just pus slushing around everywhere. You can't see anything anyway. When you add blood to that, there's no way you're going to be able to identify the source of the bleed, which is what the IR team is looking for. So usually when you have that conversation, or again, best had before you're in the middle of an acute crisis, that tends to go over fairly well. Second, there is a high recurrence rate in CF. And so this starts to impact your strategy for embolization as well. And so I think really the toughest situation that we run into most commonly is a patient has had an episode of massive hemoptysis, a CF patient, but now they're stable. Maybe you got them on tranexamic acid, and so it's totally stopped. And so what do you do in that situation? Do you or do you not continue to embolization at that point, really? And then the goal at that point in time is not to stop the acute bleeding, but really to prevent a future bleed. And so when this question was given to the guideline committee, they really could not reach a consensus. And the numbering score came out that, hey, that's probably acceptable in certain circumstances. So my approach in this situation is I do shared decision making with the patient. So I kind of look at their risks. Is this someone that had massive hemoptysis at home? The wife is right there and said he passed out, and there seemed like there were five liters in the toilet and that. That's someone that I'm going to say, hey, even though you've stopped now, we're probably going to think about doing embolization, even though you've stabilized, versus someone that is coughing up 20 cc's of bright red blood at a time, and over 24 hours, they kind of just tick over the 240 cc requirement. That's someone that I say, hey, maybe we're going to kind of pump the brakes here, because embolization is a life-saving intervention. The benefits outweigh the risks, but there are risks associated with that as well. So we don't just want to be doing this in everyone. I also push a little harder my patients with underlying liver disease. We have a lot of liver disease in our specific CF clinic that's kind of higher than the national average. So in those patients, I tend to push a little bit more on embolization as well. Advanced stage lung disease, if they have big cystic bronchiectasis, and you're like, oh man, that is definitely bleeding again. Those are the types of ways that you kind of make these decisions. So really, this comes down to shared decision making. This is a tough one and the most common situation you'll run into. And then the second thing is, so you get everyone to agree, we're not going to do a bronch. All right, fine. We're going to do the embolization. If you have a relationship with one or two of your IR physicians, this is really helpful because then it becomes a discussion. Again, no consensus really reached with the experts. With bronchiectasis from CF or other causes, when you go to look to see what can be embolized, you're going to have bilateral tortuous arteries, right? And it's like, man, you can embolize everything there. So do you kind of do a targeted approach, or do you kind of carpet bomb everything? And so there's pros and cons for each of those approaches. I will tell you that, especially in patients with advanced stage lung disease, that if you do get a little bit of infarcted tissue in there, CF patients have a billion collaterals in there, but in CF with advanced stage lung disease, those are literally two bags of pus in their chest. And if you get infarcted lung on top of that, there will be a rapid progression that often leads to death or the need for very urgent transplant. So in my patients with advanced stage lung disease, I really prefer a targeted approach. Again, discussing with the patient, with IR, do you see an area that you think is the highest risk? Let's go for that. If they bleed again, where are we going next? And kind of having this discussion, as opposed to kind of embolizing everything, increasing the risk of infarction and kind of that progressive rapid decline. But again, a really tough, tough decision. Airway clearance in life-threatening hemoptysis, again, we hold all of the devices and everything. Everybody kind of agrees with that. The nebulized therapies are a little bit more controversial. Our personal practice is, again, to hold everything but bronchodilators. We don't do inhaled antibiotics. And then we slowly reintroduce pulmozyme and then eventually hypertonic saline for our patients to kind of test them. Because again, we're using tranexamic acid right off the bat. So these types of patients, we're slowly reintroducing them, but we do hold everything at the beginning until they've totally stopped and then reintroduce them. And then I treat this like an exacerbation. Everybody's getting IV antibiotics. And then finally, lung transplant referral. Again, doesn't have to be right there in the hospital, but this is someone when I see them in clinic, I'm thinking about that as well. So really, the management of massive hemoptysis in your CF patients is really tough. Because when you are the ICU physician and you're seeing someone that comes in with massive hemoptysis, it's scary. It's like one of the few things I think is ICU physicians, where it will get an experienced staff attending physician's heart rate up, but you're detached from the patient in the sense that you don't know them. With our CF patients, we have these longitudinal relationships. We know them. We know that the risk of death is high, and it's really tough. So kind of thinking about all of this stuff ahead of time, I think really helps so that you've got a plan and you're not letting your relationship with the patient kind of bias you. So again, that tranexamic acid, no bronchoscopy. There is a high recurrence rate in CF. That's not a failure. And then we rush off to discussions about lung resection, and then finally think a lung transplant. So thank you very much, and I'm happy to take questions at the end. Thanks. Thanks, Dr. Dazenbrook. And last but never least, we have Dr. Sanjay Devrajan, sorry if I butchered that, who is going to be talking on other CF-related complications and management of this non-pulmonary critical illnesses. Thank you, Gretchen. It's an honor to be here with you. So I realize I'm standing between you and that probable happy hour, so we'll try to get through this efficiently. So my name is Sanjay. I have no disclosures. So what we're going to do is really quickly talk about the background of CF and then primarily spend our time today talking about the non-pulmonary manifestations that you may or may not end up seeing in an ICU, but these are all worth discussing. And then kind of at the end, I want to just talk about some pearls that I've kind of learned over the last few years with regard to managing pancreatic insufficiency in the ICU and how that pertains to feeds. So without getting too much into detail, CF is still considered a rare disease. There's only about 30,000 to 35,000 people in the United States that have it. The genetic mutation classically leads to what you know as primarily lung disease, which leads to most of the morbidity and mortality in CF, but the CFTR mutations do lead to multisystem disease. Now, of course, the lungs are the cause of most of the damage historically, but we've come a long way, and more than 50% of those with CF are in adulthood as we speak. So this is a population that's growing in number, and probably more than ever, you're going to have a chance to interact with one of these patients if you're not at a center than in your community clinic, or community ICU, I should say. So there was a review that came out in 2019 which looked at sort of exhaustively all of the non-pulmonary complications that are seen in ICUs. So this is a pretty exhaustive list, but I'll kind of focus on the ones that I think are probably are most probable to come across that will require either specialized management or that I can reassure you is managed not dissimilarly to how you manage other patients. So let's talk about acute pancreatitis. Interestingly, most of the acute pancreatitis that we see in those with CF are in those people who have pancreatic sufficiency. So about 85% of those with CF are insufficient in pancreatic function and will require enzyme replacement therapy. But if you look at overall pancreatitis rates in CF, they're going to be less than 2% per patient. But up to 20% of patients with pancreatic sufficiency will develop pancreatitis along the way. And the ideology of this is that essentially you have sort of sludge-like formation of the pancreatic enzymes in the biliary, in the ducts. And this can sort of lead to obstruction and sort of an autodigestion, or a brief autodigestion of the pancreatic tissue. You're not going to find a stone there, so that could sort of clue you in that this could be the ideology. And the workup is not dissimilar to what you are accustomed to in how you manage other patients with pancreatitis. In general, antibiotics are not going to be necessary unless you're suspecting that there's necrosis or an abscess. So this sounds familiar, I'm sure. And just like with those without CF, there's much more of a push, for good reason, from an evidence-based standpoint to allow these patients to have enteral feedings whenever possible, which can help maintain gut tissue, the gut microbiome, which is, as we know, is pretty important to overall health. So piggybacking on that, what about cholecystitis? So cholelithiasis is very common in CF. Up to 50% of people, if you scan them randomly, that have CF will have gallstones. But only 4% of these are going to end up becoming symptomatic. The symptoms in this population are going to be typical in terms of gallstone pathology. Right upper quadrant pain, may or may not radiate to the back. You may see an elevation in the GGT or liver enzymes. So the workup is going to be similar, it's going to be a right upper quadrant ultrasound, or if they're coming through the ER, more likely they're going to get a CT. And then the question is, what are you going to do? Well, you're going to treat these patients just like you do your own patients, without CF. A good thing to remember is that surgery is generally considered to be safe in this population with CF and acute pancreatitis, or acute cholecystitis, excuse me, unless they have severely impaired lung function. And then it's sort of a balance of the risks and benefits, as we would normally do. Interestingly, the type of biliary stones that lead to cholecystitis in this population are generally not amenable to treatment with ursodioxycolic acid or ursodiol. But you'll find that a lot of these patients are treated with this, because we really don't have a better option. And so we use it in the case, in the option that it's going to be preventative. What about liver disease? So this is one that doesn't get talked about enough. And perhaps I'm biased being, working, doing my ICU stuff at a transplant hospital, a liver transplant facility. This is the third most common cause of death in CF, being third to complications of lung disease as well as transplant complications. It tends to be more childhood onset. So the idea, the way I kind of think about this is that when you're a baby with CF and you have ductal obstruction and dysfunction, you're much more likely to get biliary stasis, and that cholecystasis. And that tends to be sort of the background issue here. So you get intrahepatic cholecystasis, that leads to direct hepatocellular injury. And then you can get classic cirrhosis and even get portal hypertension, decompensated cirrhosis in these patients. So what do you do if somebody comes in with an acute liver injury and you see really high liver enzyme levels, AST, ALT, greater than five times the upper limit of normal? If they are on one of these CFTR modulator medicines, you generally want to hold those in the acute setting, if there's an acute liver injury. But if there's an acute on chronic injury, it's the same principle. You want to rule out secondary causes, as you would. Things like autoimmune hepatitis have been described in CF patients. You want to look at hepatitis. You want to look at alcohol use, other medications that are hepatotoxic. If sometimes, usually not in an ICU setting, but an inpatient setting, if we're trying to figure out if there's another etiology in somebody with CF with liver disease, we sometimes will get a biopsy before they can be considered for transplant. And what this usually shows is very focal portal fibrosis. If you have a patient with decompensation, they can have variceal complications. They can have variceal bleeding. So these patients are eligible for tips for emergent bleeding. And in a situation like that, this would be a really good opportunity, if you're not at a transplant-capable facility, to transfer them to one that is, so they can be considered. Diabetes complications. So this is probably an underappreciated part of CF that, as we're seeing a lot more patients in adulthood, we're seeing a lot more of. The prevalence of cystic fibrosis-related diabetes is 30 to 50%. And this is primarily seen in adults. And the physiology of this is quite different from type 1 and type 2. Some people refer to it as type 3. And the ideology is, because of the pancreatic dysfunction, the pancreatic insufficiency, you can get islet cell dysfunction. You can see delayed or reduced insulin secretion and production. So there's a lot of curiosity as to whether the CFTR modulators have an impact on this. And probably, at best, they have a very modest impact, if at all. So this is going to be one of those things where, even though the lung disease bit of CF can be well-managed in somebody on CFTR modulation, you're still going to be left with these extra-pulmonary manifestations, like CF-related diabetes. So how can this manifest? It's not uncommon to see somebody with raging, wildly uncontrolled CF-related diabetes end up in an ICU on an insulin infusion, because they're dehydrated. They have electrolyte derangement. So this can behave very, very similarly to type 1, or it could be sort of like an HHS, starvation ketosis kind of situation. But if somebody comes in with a blood glucose that's undetectable, my bias usually in these situations, because I do find that CF diabetes is a bit more brittle to deal with than some forms of type 1, and certainly type 2 diabetes, that I do sort of err, if they're coming into an ER setting, to actually put them on an insulin infusion, especially if we don't know what their insulin requirements are, to try to get a handle on that first, and then safely get them out of the ICU. They also, the primary treatment for CF-related diabetes in the outpatient sphere is actually insulin. So we don't often use the oral diabetes therapies for these patients, because of the pathophysiology of the disease. But they do end up on, in some cases, very high doses of both basal and preandial insulin. So we do see hypoglycemia in these patients, and that could be another avenue for them to end up in your ICU. The picture I'm showing you here is a fairly classic picture of another complication, probably the most well-known kind of extra-pulmonary complication. And what you see here is, is this a pointer? Oh, I won't play around with this, right? Apparently not. What you see here is in the distal colon, which you can see on the left side, you see a lot of impact at stool in the colon. And you see this sort of proximal transition point, where you see a lot of gut contrast and a dilation of that small bowel. So when you put this together, this is very classic for the distal intestinal obstruction syndrome, or DIOS, where you have a lot of CFTR expression in the gut, and you get a lot of viscous mucus in the stool, and you can get an obstruction. This is primarily seen at the ileocecal junction, so that's where these transition points, if you're able to see them, are usually going to happen. And they're not that uncommon. If you have a kind of a combination of somebody, you know it's somebody with CF, they've got a palpable right lower quadrant mass, abdominal pain and distention, there's not a lot of other things this could be besides DIOS. But those things are acute appendicitis, you can't overrule that, or you can't rule that out. Constipation, just severe constipation, if the patient's not vomiting, then this may be just a severe episode of constipation that could be amenable to stool softeners. Intussusception can be seen even in the adult population with DIOS, and it can often be seen on ultrasound or CT scan in these patients when you image them in the moment. And it should be noted that colon cancer, it appears, though not the highest quality data, but the data that we do have from case series and retrospective studies is that CFTR plays a tumor suppressor role in the gut, and so people with CF actually have higher risk of colon cancer, and therefore are generally screened for colon cancer earlier. And so malignancy can be sort of a predisposition to somebody getting obstruction in these areas in the proximal colon. So this can be evaluated through an X-ray or a CT. The risk factor for DIOS, generally if you have more severe CF, you have a higher risk genotype, or you have pancreatic insufficiency, those are going to be your top two background risk factors for developing DIOS. So like I was saying, if they're not vomiting, you really don't treat it like you would a classic small bowel obstruction. You can actually treat through this aggressively with oral laxatives. Polyethylene glycol is probably the most common one that we use, Go Lightly, as the name would go. You can also use oral gastrographin to push through it. If they're vomiting, now that's when you want to pump the brakes and avoid that strategy. You generally want to nasogastrically decompress and treat as you would an SBO, a complete SBO, with IV hydration, in some cases pain control. If you're in an experienced center where you have a radiologist that's capable of performing a gastrographin enema, that is a consideration. I've never actually been able to get this accomplished at my facility. And then last but not least, if you're not able to sort of treat through this conservatively, getting surgery involved early is sort of important here. And there have been reports that they can actually laparoscopically resolve these obstructions without resecting bowel, which of course would be in the patient's best interest, if at all possible. What about other organs? So nephrolithiasis is, kidney stones are more common in those with CF than in the general population. And the real big reason, we think, for this, based on the data, which is not the greatest that we have, is that those with pancreatic insufficiency have an excess absorption of oxalate, which can build up in the bloodstream. And so you have actual elevation of oxalate in the urine, which can crystallize, so you can get calcium oxalate crystals. These are infamous for being harder to treat from a lithotripsy standpoint. So there's generally a higher incidence, or higher requirement, of surgical intervention in these larger calcium oxalate stones in CF than the standard calcium phosphorous stones that you see in the general population. But your primary treatments for these are going to be hydration, pain control, and get an experienced urologist on board. Catheter complications, I don't need to talk about too much. It looks like there's actually, despite the significant amount of antibiotic usage in this population, the actual complications from peripherally inserted and central catheters is actually fairly low. Probably the most common complication you're going to see, either in an ICU setting or as we often see in the outpatient setting, is occlusion in your peripherally inserted catheters, which can be managed with local TPA. What about anaphylaxis? Due to the higher cumulative antibiotic exposure, you could see more unearthing of antibiotic allergies, which can end up with patients in anaphylaxis. The management is going to be the same as the general population. Likewise, if they have a lot of known antibiotic allergies, it may not be unreasonable to bring these patients into the ICU for a protocolized desensitization. The data that we do have on this shows that about two-thirds of these desensitizations in CF will be successful. So this can be really a fruitful way for this patient to spend time in your ICU. AKI, acute kidney injuries, yet again, another sort of complication of liberal antibiotic use, primarily the use of aminoglycosides, because tobramycin tends to often be part of the dual anti-pseudomonal regimen that people get. So what are the risk factors here for people developing acute kidney injury? Well, the primary means, by the way this happens, is going to be intrinsic kidney injury, so an ATN-type physiology. But I have found that you can actually manage these pretty well with planned hydration, before and after antibiotics. But generally, if you have baseline CKD, which the bench work in CF has demonstrated, these patients have a lot more subclinical chronic kidney disease than the average population. That can actually, even with a normal creatinine, they can have baseline CKD, which increases their risk. Dehydration, the presence of CF-related diabetes, a prior history of acute kidney injury, especially on a particular antibiotic regimen and dosing, can clue you in on what doses are safe. And of course, you want to stop any nephrotoxic medicines if you were to see this occur. So you're going to stop the offending agent, you're going to provide some hydration, because most of these patients are young and can afford volume challenges. And I have found that the majority of these cases can be sort of managed in an uncomplicated way just with this strategy. The need for dialysis in this population is not zero, but it's rare. So let me end with just some principles of pancreatic replacement therapy, because this may be something you deal with in the real world. So let's talk about some scenarios. So scenario one is, you've got a patient in the ICU with CF who can eat. So they've been taking pancreatic enzymes since they were children, so they have their regimen burned in their brain. So if they're able to talk to you, make sure you ask what their enzyme regimen is. If they're allowed to eat, let them eat, and make sure that they have access to their replacement therapy. The basal metabolic rate of these patients is higher, historically, because of the worse lung disease and multi-organ involvement. So they generally have a, because of their higher basal metabolic rate, they tend to be catabolic very fast. And so there's guidelines to suggest that we really should be allowing these patients to have high-calorie and unrestricted diets. What about the second scenario? So the patient cannot eat. So if they're not getting any nutrition, that is, if they're not getting any interior nutrition because of obstruction or the like, then generally enzymes are not required. The complication is that they generally cannot absorb their CFTR modulator medicines or other vital oral therapies when they can't eat. What about scenario three? So let's say the patient's on, has been intubated, and is receiving continuous tube feedings or spot tube feeds. So what can you do here? So there's a few options, and this is tough because this is not always easy to execute. So if you can, with these tube feeds, you can actually give them scheduled enzyme replacement therapy every four to six hours, but they can't eat. So what can you do? Well, the manufacturer guideline is that really you shouldn't crush these enzymes because they lose their activity. But one thing you can do is actually, you could dissolve it in small aliquots of D5 or normal saline, and you could actually open these tablets and dissolve them. The problem is when you have a small tube, they tend to crystallize very quickly. So something like a DABOF tube will very frequently get obstructed. But if you have a larger-bore nasogastric or orogastric tube, you could do that, and you could basically time the enzymes every four to six hours. But this becomes sort of a logistical problem, especially if you've got a nurse that's not experienced. There is a product that basically immobilizes pancreatic lipase or synthetic lipase in cartridges, which you can actually put in line with the tube feeding. And basically, as the feeds traverse this cartridge, it actually carries these enzymes in with them. So that's one, if you have that available through your hospital formula, that is an option. So again, by manufacturer guidelines, you really shouldn't crush or dissolve these enzymes. But I do find that it has been a practical solution sometimes, instead of dealing with endless diarrhea and malabsorption in these patients. And to sum up, CFTR modulator therapies have really changed the playing field. So we're seeing a lot less morbidity, and what we expect will be mortality in CF from a lung disease standpoint. But some of these extra-pulmonary manifestations, we really don't know what these modulators are going to do for those things. So I think it's more likely than ever that you're going to encounter one of these non-lung issues in your ICU. If possible, allow patients to eat, don't keep them NPO, because of the fat solubility of these CFTR modulator therapies, it's vital that they have nutrition to be able to absorb this stuff. If you're using tube feeds, make sure that you're providing them pancreatic enzyme replacement therapy in some form or fashion. Just like with other medical ICU patients, you want to allow for as much mobilization as possible, which is a great adjunct to airway clearance. And these patients are complicated, so make sure that you, as Dr. Dasenberg mentioned, you want to really get your pharmacist involved in the care of some of these patients, because they can really help you walk through things. So thanks for what you do, and I'm around for any questions.

non-pulmonary complications

management

cystic fibrosis

ICU

acute pancreatitis

cholecystitis

liver disease

diabetes complications

distal intestinal obstruction syndrome

CFTR modulator therapies

CF