Dr. Rajeev Bhatia assessed the risks and benefits of commonly used medications for infants with BPD, as well as at the individual level for the specific patient.
It's uh my pleasure to introduce uh Doctor Rajiv Bhatia, who's our division chief of Pulmonology and our co-director of our BPD center. Uh He's uh prof uh associate professor of PD or at the College of uh the University of Arizona College of Medicine and also at mail uh and a good friend. So uh please welcome Doctor B. So I used to start my slide saying that I'm not that popular to have a disclosure, but funny enough that I have a disclosure which is relevant. So I don't know. So I'm, I'm a consultant for Merck manual. So I write chapters for them or update that. So some of because we were discussing pharmacy. So, so this is was reviewed by CME office and it is uh there content found to be evidence based balance and non promotional. So I want to make sure. Ok, so uh we are going to talk about um the utility of bronchodilators, steroids and uh other inhaled meds. So as as you can see, there are not much evidence for other medications, the evidence in this is even further less. So just I want to make sure I will. That's why I made sure I have few slides where I have discussed, what is our approach, which also you have to take with a grain of salt, which is based on what we have been doing and whatever literature we have. So I have a little funny story to start with because when I was a fellow, we had a patient with cystic fibrosis who uh was asking to uh put chapstick on her lips and she was on oxygen and her to the extent that her lips were bleeding. But the respiratory therapist would not let her apply Vaseline or other things because he was told that a patient on oxygen applies when they, they can't apply Vaseline because it's a fire hazard. So we couldn't find it. So we said, OK, who has told you that it's a fire risk? And he said, 01 of our RT head had a, she, she is a big, you know, you know, had a lot of publications and she has always told us. So we went to her. So my mentor sent me to her and say, you know, ask her why, where did she find it? So she actually showed us a paper which she has written without any references. And in that she has written that it's a fire hazard. So the reason I bring this up every time that we have to have a balance between evidence based and some assumptions too, I think the discussion, what we are doing today is not, we will, I will not have answers for all the things, but I think this is just a challenge, our assumptions which has been, you know, carried for a long, long time. So we'll start with um Inhale Bronchodilators. Um As we all know, there are a couple of Inhale Bronchodilators, we use one is Albuterol. Uh The broader category is beta, two agonists and anticholinergics. So, the beta two agonists are albuterol and albuterol and albuterol. Um the albuterol has two isomers R and L. Um that albuterol is um there is, it's believed that it is only r isomer because that's what causes, that's what is needed for bronchodilation. So, since it does not have the other isomer, it has less side effects. So we tend to use albuterol more often than L albuterol, but we have to use that also. So, but we know that it decreases airway resistance through bronchodilation and improves the radiation. But we also need to remember that it does cause side effects. We have tachycardia, blood pressure and increased risk of tachyarrhythmias. So I could not find any big good studies. Um I know Dr Baer referred to one of the other studies, but the, the biggest study I could find is this 87 infants who were randomly assigned for placebo versus a chronic beta two, a therapy. They did not find any difference in mortality and this and the rates of severe BPD was also not different. And this, actually, this study is also long, at least 2030 years old. So we don't have any recent evidence to show whether inhaled broncho are useful in, um VPD. So at this point, as I said, I'm going to go over where, what are our recommendations? I, we usually don't use chronic beta to agonist and we don't think it improve outcomes. However, there are studies to show if it is a severe BPD, especially in old infants, they can have acute episode of bronchial bronchial constriction. And we'll talk about that. That is, we call it BPD exacerbation. And those are because remember BPD is a state of inflammation, any state of inflammation, increase your airway reactivity, whether you call it asthma or not, that is debatable, but it does increase the airway reactivity and these kids can have proper constriction. So if um a baby is having a significant Bron bronchial constriction, it is OK to use bronchodilators for to improve short term lung function, short term lung function. How can you do it? You can do both nebulizer or MD. I traditionally, in our practice, we say MD is, are better, but we have always been um whatever is easier. That's what we have promoted in our, in our NICU MD I is tend to have a less dose which is considered to be more efficient. But as I said, we allow any route, whichever is easier. And as we were discussing recently that. How do you say the patient is getting better? So it's you might not. Um So we there are a lot of clinical ways you can see that. So, and that's how we go by because you may not not, you may not see improvement in oxygenation, but you might see decreased work of breathing, um decreased effort, improve lung radiation when you listen to the baby. So if the patient has a good response, we let it be for a few days. But as we were mentioning our mother, that is three rounds, especially Rhonda, she always brings that up is that his patient has been on albuterol long enough. Are we making it pr So that is really important too. So then the next one is ipratropium which is an anticholinergic agent and that can reduce from the constriction and excess secretions. So where do we use tropi? I couldn't find any good studies to specifically look for Etro pum in BPD patients. So I here I would just extrapolate what we usually do in our other patients. So Etro pum we tend to use if we are worried, especially kids with bronchomalacia or um they are if they are on a beta blocker because then the beta two agonist would not be um beneficial. And there are um there is a possibility that you can worsen bronchomalacia if you're using a beta two agonist because yeah, it's um because of dilation of the smooth muscle, but we know that a petroleum has side effects. It obviously anticholinergic, it um decreases the gastrointestinal mortality and also can thicken secretions. So, especially for severe BPD who are tr and when dependent. So be careful when you're doing the uh epi we have used in combination with albuterol, but I couldn't find any good studies whether one is better than the other. So mainly we use a petroleum if we think the albuterol would not be effective or if we think patient has tracheobronchial Asia. So that is a really good segue into tracheobronchial Alaia. Why I have this slide in our pharmacology uh presentation is it is really important for us as a BPD providers to differentiate that we have had a lot of patients on bronchodilators and other medications where uh the main problem is tr your bronchomalacia. And I think there is a lot of uh movement now to uh find because we have been um finding more tracheobronchial in these patients. And I think just because of them being on bend for a long time. And that's why there is also a lot of movement who are collaborative to do more bronchoscopies in these patients to identify uh these abnormalities. The way I teach the residents is that it's very, very difficult to differentiate whether that prolonged expiration is due to bronchoconstriction or is Malaysia um clinically what you can, how you would differentiate is that if it is more central and is it if it is more monophonic, then it's likely trachoma versus if it is more peripheral, it's more broncho striction. It's easier said than done when patient is un vent and the course breathing. But just to differentiate sometimes if it is more episodic, that also is Malaysia. So you can clinically differentiate. So just be cognizant of that, that it can be there. And as I was saying that if it coexists with um where if your bronchial constriction and if your airway reactivity and Malaysia is coexistent, which could be in many of these patients, then you try to, I try to use a petroleum instead of beta two agonist. Ok. So we have covered the easier part. The difficult part is this one as if you are not confused enough with previous presentations, let me confuse a little bit more. Ok. So we, I think it was very tempting and um to try inhaled steroids in BPD patients because as you saw a lot of studies with systemic steroids, there were a lot of side effects that they said, why not? We should go for inhaled steroids and which hopefully has less side effects and may be effective in mortality and other things um similar to systemic systemic steroids. But unfortunately, we haven't found that much of an effect um is not consistently shown to reduce um BT D and also probably increases the risk. And I'll, I'll briefly talk about that. So in, in this meta analysis of six trials where they gave inhaled steroids in the first two weeks of birth, they did not see any difference in the rates of BPD. And also the mortality was also very similar. However, when they looked at the survivors, it did reduce the risk and the adverse events were similar. So at this point, people started to think, ok, maybe it's not as bad we can use it, it did reduce the risk and the adverse effect were similar. However, in this meta analysis, the, the um the biggest trial was a neurosis trial which we all know is published in New England journal in 2018 and they used in Hilbert. And what, however, this study showed that when they followed the kids for two years, um there were more deaths in the patients who were on it here still. So and although ND I rates were similar. So overall, it was not um without the significant adverse events. There, there is even fewer data to uh about when you are using inhaled steroids later, more than seven days after birth. And in this meta analysis, they, they did see that patients who were um who were given inhaled steroids after seven days uh were less likely to be remain to, to remain intubated. Their, although their duration of mechanical ventilation was similar and there were no firm conclusions because there was a lot of inconsistency between these trials. So they could not make a firm um conclusion on mortality and rates of EPD and other serious events. So, as I mentioned, I will briefly come back to what we tend to use. And um so we do not routinely use for prevention of EPD. Um And part of this is we don't even know how many of them will develop BPD. So to, to expose everyone to these steroids where we can have more side effects, which we did not think was reasonable. So we don't do that. And as on our BPD rounds, we do um look into some of the older patients who have already had severe BPD, who are already on substantial respiratory support and may or may not have evidence of air radioactivity. So in these, we do tend to start in health steroids to reduce the lung inflammation and hopefully facilitate the ventilator. So we talked about uh prevention and, and I briefly talked about that, where do we use in established VPD? So there is a term, as we know is a VPD exacerbation. Many of these kids do tend to have airway reactivity. So as in our BPD rounds, we evaluate that and we do tend to start them on beta agonist, either they are PR M or we put them on for a few days and kind of wean it off. But it's also really important to re evaluate with every um VPD rounds or every few days to make sure they truly need every 4 to 6 hours or can we wean them coming back to that question, which was asked earlier? So I did not, I couldn't find anything in particular that instead of dexamethasone, if you could use prednisoLONE, but we do use predniSONE for established PPD. Who have we found that they are, um they have evidence of air reactivity and beta two agonists have help. So, and if they're already on inhaled steroids, then it may not be unreasonable to give them a short course of steroids so that we have done. Um But obviously, we limit that that to an older babies who are older than 40 weeks and were, you know, concerned for side effects, they still could have um adverse effects. But we hope that the benefits outweigh the risk. I'll briefly touch upon some of even, I mean, if for the zebras where we can try these, some of the other medications have come into picture just because we have tried to use that in other fields. So one revelation for me, in particular, since I've been part of BPD for many years is that a few patients I have wronged, they have sometimes secretions thicker, um even thicker or even similar to what we see in our CF patients, which I have never realized. And I'm not trying to say that this could be in every patient, but sometimes we don't realize that that could be, they can have that take secretion that much information. So that kind of brings us to whether we can use a similar mucolytics which we use in our other population, whether it's AC F or patients with ALETA is for older patients, inhaled hypertonic saline, we use sometimes it does reduce the vee and mucus thickness by Boity. Um As because we know that they are thicker secretion in BPD. Can we use that? We have, I would not recommend routine use, but we have tried to use it with our patients. Either we have seen a significant objects um or you know, significant thick secretions to see along with a chest pt to see if that could help. We have some anecdotal evidence in some patients. It helps in some patients. We have made it worse just because remember it's a big irritant and some it can cause bronchospasm too. So sometimes we have even made things worse. So I don't have any particular data, but this is something to think about if you have a patient with significant Atlantic. And similarly, syste is also we have used in patients, especially uh with a lusis in older patients, which it hydrolyzes disy by bones within mucin and breaks down that mucus. It's very tempting to use it for a severe BPD if you see a big thick, a big, you know, a lactic. However, it's also very, very irritant. So we have to be careful that we don't want to use it for every patient. So, but selective patients, you can think about that. Um I would not recommend obviously a regular use um that brings to another um inhaled medication which is Garnes alpha. It's a recombinant enzyme. You might have all heard in cystic fibrosis that has been routinely used, it breaks the bonds between the DNA, which is derived from leukocytes and infectious agents. Um And actually, there are some case reports um which have shown the utility in Pritam babies, not particular for sever VBD, that it is used for neglect. Again, it's very tempting if you see a patient who has the GIS to use it in our, especially at some trachea bent patients. Um Honestly, we have tried here and there, but it's not as useful and we think it is not cost effective too. You have a much cheaper mucolytic drugs if you really want to use for non CF patients. I we don't think it is actually useful. So here, I'm just gonna quickly show uh um an abstract which is actually mainly um Rhonda's work and groups. I've just been PTI involved where um which is not related to CBPD directly. But I just wanted to highlight this because as we have these medications, as we were talking that there is always urge to use more and more. Um this was actually a few years back, we realized that we have been using this Adonis Alpha in non CF patients uh quite regularly in pu uh which we did not think was useful So we made only a small change where we said after certain doses, the IC U or whoever is started, it has to consult Pulmonary and just making that small change doesn't make them just uh making them to think a little bit before they could just continue that forever. Um had made a huge change. We have seen a big decline and as you can see, it's almost 100,000 um of cost saving just because of that. And not even talking about all the side effects and other things which you can cause. So just bringing home the point that, you know, if certain drug is effective and certain disease doesn't need to be effective in another. And even if you're trying to make sure you just, you know, going back and making sure it's not been used forever other important medication uh INH doro Mycin again, extrapolating from cystic fibrosis patients. I don't have any significant data in, in um CBPD patients. We recently put a patient which was actually not BPD, but we have other conditions um because this patient was growing pseudo one as a trachea vent patient and we put them on um in Toro Mycin. That also, as I said, we u we do not use routinely if uh in tr and when patients who have chronic colonization, whether you should use it for some time, you can, we have tried it every two weeks on two weeks off or one month on one month off. Um It's very hard to get approval outside of the NICU as an outpatient for any non CF patient. So remember that also, but I don't think it is unreasonable to try that for a short term in the in the NICU. If you are struggling with um chronic colonization, the want. Um although this was not. So I I just include this slide. Actually, the last year I gave a talk about long term outcomes for our CBPD patients. And this is actually a slide from that presentation. And I thought that will be relevant in this presentation too because we do put patients on inhaled steroids and albuterol. And there is, it's a big conundrum. We don't know how many of these patients is truly going to develop asthma or just an asthma like symptoms or how long should we keep giving these inhalers as an outpatient? So, the studies, there's the biggest study was epicure study which looked at age 11 and um at that 0.25% had diagnosed with asthma and which is one out of four. and then in, in BPD patients and then almost half had abnormous barometry actually. But the what they, sorry, what they found is that these are not truly as one, this is a fixed obstruction because they did not see their pheno was high or they did not see much air reactivity. So, is it some chronic change which happens in these BPD patients, which is not uh responsive to inhalers, it's very likely. So, and there's a lot of genetics into this too. Some may truly develop asthma. So what I'm trying to say here is that don't automatically think that every patient who has BPD, who may need inhalers in the NICU truly is asthmatic. So that, that's the only point I'm trying to make. So what do I do or what do my colleagues do for these patients? I, what I have seen is that the symptoms tend to improve as they get old. So many, I would say um almost 75% of the patients are able to or at least 50 to 75% of patients. I'm able to wean them off after maybe close to their one year of life. My approach is that if it's milder BPD, they are doing well and specifically, if they don't have any risk factors, they, there are studies to show there are two major risk factors for asthma, uh patient having eczema or one of the parents having asthma. So if none of that is there, I usually uh discontinue the inhalers. Um But if it is a sicker patient or especially if they have a risk extra asthma, I tend to keep it longer and then we decide whether uh they need it in the future or not. I think that's pretty much it. My, like my talk was not too, I would say evidence based because there wasn't much evidence. So I thought I tried to keep it clinical because I thought that could be the most beneficial. So, if I were to, since I to summarize, I think inhale bronchodilators, you don't want to use chronically and you can use it for air with the activity, but keep it short term inhaled steroids. There is no much data for the early inhaled later, you may use it, especially if it is a severe BPD who is dependent to reduce the inflammation. You can also use um inhalers, especially beta two agonies for exacerbation. Um And then there are some other medications which is inhaled, Tobramycin, Dorna alpha and other mucolytics, which can, which we can use it here and there. But there is no evidence uh for a regular use. That is it? Thank you.
