NeoDose–The Past, Present and Future of Neonatal Pharmacotherapy with Lianne van Bussel, Dr Robert Flint and Dr Sinno Simmons

00:00:00: Welcome to Neonatology

00:00:02: Now,

00:00:02: the official podcast of The European School Of Neonotology.

00:00:07: Here at Neonautology Now we are shining a light on real-world experiences of world renowned experts in perinatal medicine.

00:00:15: Together We will learn from top medical doctors researchers and opinion leaders To better understand how can improve

00:00:24: professional neonatal care

00:00:25: In Europe

00:00:27: And beyond.

00:00:28: It's not

00:00:28: just about science.

00:00:30: It's about the stories and experiences shaping this critical field of medicine.

00:00:36: And now, without further ado let me introduce you to your host a seasoned neonatologist.

00:01:00: Today, we are diving into one of the most important and often underestimated aspects of neonatal intensive care – medication dosing in preterm

00:01:10: and termed neonimism.

00:01:12: I am Professor Rudiger and my guests for today is Diana Brasl, Sino-Siemens

00:01:16: & Robert Flint from The Netherlands.

00:01:18: Despite incredible progress in Neonatology many medications used in the NICU are still prescribed off-label and dozing practice varies significantly between hospitals.

00:01:31: I guess today are helping to change that.

00:01:51: And their work combines clinic experience, pharmacology and an international collaboration to improve medication safety and efficacy for our small patients.

00:02:07: So Liana, Robert & Sino I'm very happy to have you here!

00:02:10: And i am very happy that your going introduce yourself or each other... ...and so I start with Liana whom you want to introduce?

00:02:21: I can introduce Sino So now he's head of the department of neonatology and is a Neonatologist himself as well as a clinical pharmacologist working at the Erasmus Medical Center.

00:02:36: And he's very interested in pharmacotherapeutic research on drug development for newborns, I learned that he has special interest in analgesia and sedation.

00:02:47: Thank you for the nice introduction.

00:02:49: i'd like to introduce Robert then.

00:02:51: so robert flint this A hospital pharmacist that I know for a very long time, we collaborate on clinical practice but also in doing research.

00:03:03: And it is fantastic to have a hospital pharmacists who are really interested in neonatology.

00:03:09: He did lots of research and good work to help our little babies To have better knowledge about how to use drugs in preterm critical infants.

00:03:22: Really nice to have robots here with us.

00:03:25: It's always good for pharmacologists as a collaborator because that is an expertise Neonatologist almost never has.

00:03:32: and so Robert, welcome to the podcast!

00:03:34: And it's up to you now to introduce Liane.

00:03:38: Thank You very much, I'm happy to be here as well.

00:03:40: thank you for the kind introduction.

00:03:43: Yeah, Liane is a PhD candidate at the Robert U. Medical Center.

00:03:48: she has background in biomedical science especially focused on pharmacology and toxicology.

00:03:55: And she's very passionate about applying these fields to make an impact on clinical practice of how we optimally use drugs, so you treat the most vulnerable patients?

00:04:08: Okay!

00:04:09: So now I know there is a professional background for my guests in order you much better.

00:04:19: I always ask for a special anecdote in your professional or private career, Sino.

00:04:24: So is anything... You can report to our listeners about it?

00:04:31: Yeah of course!

00:04:33: I thought about this and i think to me um ...you just said that there's not a lot of neonatalists interested or really expert in pharmacology .I really thought Doing research, but then in clinical practice proper falls introduced as a new agent that could be used to as a sedative or an aesthetic before endotracheal intubation.

00:05:01: And it was paper out and the implementation so rapid.

00:05:04: so within week everyone is using pro.

00:05:07: for me I was really intrigued by how easy we just took the drug because it was easy to use into clinical practice where I thought, okay but do we know the pharmacokinetics?

00:05:18: Do we know that dose?

00:05:19: what's?

00:05:20: the difference is a baby on day one and fourteen.

00:05:23: And so yeah i think it motivated me to ask these questions and to think about how neonatology started to use medicine.

00:05:31: uh... But also really find out if you can do better.

00:05:38: No before we introduce a drug into clinical practice on how you should use the drug and what would be.

00:05:43: A good way to dose it, yeah so from thereon but also for a bit I was really interested in knowing more about how drugs work.

00:05:53: little babies

00:05:56: i think that distinguishes you form many other neonatologists who love to adapt just uh drugs from adults or from emergency care.

00:06:06: Think very much about the special situation newborns.

00:06:11: Yeah, so I thought about it.

00:06:13: But then if you are interested and you stay interest probably because there's so many questions that still open sort of kept Keeping my interests yeah?

00:06:23: Yeah That's good.

00:06:24: So Leanne your very young.

00:06:26: and so for what influenced you?

00:06:30: um What influenced me, actually to say was this project.

00:06:35: This new doors projects got me into neonatology.

00:06:38: I was always interested in pharmacology.

00:06:42: They said we have a really interesting project which involves pharmacology.

00:06:48: It sounded pretty simple making just those recommendations A lot but still quite simple.

00:06:56: and then i got hit with the complexity got me really interested.

00:07:01: Is that there's so much complexity, but still they're so much also to resolve?

00:07:07: and it's not that we cannot resolve the complexity that is there?

00:07:11: We only need to understand this.

00:07:13: So... It's what got me very involved into that And I could really help along the way from new neurologists such as Sinnoh But also the pharmacist Robert who got me guiding through that path.

00:07:29: Okay And now I'm very curious to hear from a pharmacist any special experience or an anecdote for your professional career.

00:07:41: Yeah, so my passion for pediatrics and enatology started during my studies of actually before we studied as pharmacists but when i was a pharmacista wanted to work in the hospital.

00:07:54: it started by education residency to become a hospitable pharmacist.

00:07:59: That's where I really got involved in a pediatric hospital.

00:08:03: In Amsterdam, this case and i was surprised that we have these little booklets formularies And several big pediatric hospitals in the Netherlands They published their own pediatric formulary.

00:08:22: So you had one from Utrecht One from Rotterdam One from Amsterdam ten versions in your own hospital and everybody was writing these notes.

00:08:32: In his own book with the new findings or new consensus that they found how we could optimally dose, allow a dosage for even most vulnerable pre-teenborn infants.

00:08:45: so you had many version of this book Most notes in it.

00:08:53: so that colleague.

00:08:53: That was most extensive inviting with writing enough to see whether you can check and allow a certain drug or find information, and There was the starting point there where I always thinking okay is this then?

00:09:06: Where we bring our knowledge as a pharmacist two to the ward And they're at the same time Two seven ten.

00:09:14: the pediatric formulary was yeah getting start.

00:09:20: I got involved with people like Sinnoh and others who were working from the field.

00:09:25: And then combining this knowledge that we were capturing in a book, with notes into an online published formulary which is really... ...the best evidence and consensus for the country.

00:09:38: So it was very nice starting point at a circle that closes here.

00:09:46: That's a very nice segue to my first question which is a kind of historical background.

00:09:51: You know, for many years neonates were often described as therapeutic orphans because so many drugs lack neonatal studies.

00:10:00: but why has neonatal pharmacology historically lagged behind adult medicine?

00:10:05: And furthermore what have been the consequence in daily NICU

00:10:09: practice?".

00:10:11: Yeah I think it's quite difficult question.

00:10:17: Well, I think doctors just needed drugs before they were studied right.

00:10:21: so People in the past.

00:10:23: Just started treating preterm babies younger and younger without having knowledge on how drugs would work in these pre-term babies And They just needed certain drugs and then extrapolated knowledge from older children or adults.

00:10:39: So i think there was just a need for drugs enough knowledge and that's something we still encounter I think in clinical practice sometimes.

00:10:48: But over the time, we've learned more how small babies work and what is needed to provide them with adequate dosing.

00:10:57: but it also of course that drug research really takes a lot of money.

00:11:04: so there's definitely resource.

00:11:07: part.

00:11:09: A new idea up to a registration is so complex and expensive that it's often not just good business case for preterm infants.

00:11:20: where they are small, there isn't a pharmacy company or whatever behind them.

00:11:26: So its different parts maybe led into this situation but might also be us as you said maybe often early adapters.

00:11:39: And if someone has a good idea, we just start and think okay let's go!

00:11:43: If it works its probably good but yeah...if you look at the consequences of pre-term birth for instance in their long term potential negative effects there might be still lots to gain right?

00:11:55: So I've thought that although you may think that a drug works appropriately and have no side effects they're.

00:12:04: That's

00:12:07: a very important aspect.

00:12:08: So maybe you see an immediate effect, but nobody is really looking at long-term effects because You cannot Contribute these long term affects to the drug you have given and that's a problem.

00:12:22: It's fairly complex right?

00:12:23: And it's also very difficult in Compared two adults.

00:12:27: so we don't have healthy preterm volunteers Right now.

00:12:30: its always a complex situation.

00:12:33: we have critically ill babies with multiple comorbidities and well, so it is a difficult situation in very vulnerable patients where this difficulty to study certain stuff.

00:12:48: So Deanne do you think the younger generation of neonatalogists today fully appreciates how much or appreciates or is aware of how much uncertainty historically exists around dosing?

00:13:02: We just take for granted.

00:13:04: I think that's a very good question.

00:13:32: less certainty nowadays because we have jerks that are being studied with, for example from kinetics and from code dynamics.

00:13:42: Because we have less invasive research or sampling designs than you have a more advanced statistics so we can do even more now in studying some drugs.

00:13:57: So I think it already has been improved i think form decades ago.

00:14:02: but Yeah, I was not around then sir.

00:14:09: So Robert you already described the situation.

00:14:13: so every unit has their own handbook or something?

00:14:17: Was there any critical moment where you really realized that national harmonization is urgently needed?

00:14:29: We had this already on our list for a long time to specifically dedicate our attention To the neonates and Peter and born infants.

00:14:38: But at first there was the big focus of all infants, and do as much as possible.

00:14:43: So it's on point.

00:14:47: we Got ourselves into the situation where I could get some money too.

00:14:52: Get this done because also a signal mentioned that always asks time and dedication Of the people that you need.

00:14:59: it's not just us three, its a whole pool also depending upon the drug that you're discussing for an antibiotic.

00:15:06: You'll also want to involve um uh a microbiologist or somebody who is really from that background.

00:15:13: so they need to have time and bit of compensation with money too.

00:15:19: get them done usually because she also wants do it for many drugs.

00:15:24: So there are only one drug in this case.

00:15:26: So fortunately, we got money to do the first project and the first fifty-sixty drugs.

00:15:39: And then did that for another pool of fifty-Sixty Drugs... ...and now we get it up to speed.

00:15:45: so you also maintain all the recommendations for the drugs that are currently using in the Interpractors.

00:15:52: That's actually how we could really on such a big skill for new units as well.

00:16:00: So you know how difficult was it to bring together clinicians, pharmacists and researchers from all I think almost all Dutch NICUs into one collaborative

00:16:09: framework?

00:16:13: And actually it was relatively easy in the beginning.

00:16:17: so i think from the beginning we had pilot project in the past where everyone really felt that this was a good idea, right?

00:16:24: So everyone probably noticed what also Robert mentioned that we all were doing kind of the same but there are quite some differences.

00:16:33: And so in the pilot project couple years ago it was tried some enthusiasm and I think with the years is difficult to keep everybody on board because as many things do why would you prioritize talking long time about drugs?

00:16:51: I think this is another challenge of this knowledge gap in appropriate knowledge on drugs for neonates, that it's not really sexy.

00:17:03: Pharmacology always has a topic.

00:17:07: most neonatologists and doctors are probably not very interested.

00:17:10: they like if someone else tells them what to do.

00:17:14: It's my opinion.

00:17:15: but also when you go through conferences it's difficult to have people in the room for a pharmacology section, right?

00:17:22: So we know I was involved in the Pharma Section and ESG and we also always knew or knew that you should better take another title.

00:17:30: Right so F them in with clinical trials but don't mention Pharmacology because... But In this project And To be honest i think there were at least a new network just from every NICU in the Netherlands involved Of course in busy schedules sometimes challenging, but I'm really proud that we managed to have everyone on board and get the information from all of the clinics.

00:17:56: To enable Leana to have an overview then talk about these differences and see where their consensus would be based on knowledge or evidence?

00:18:10: So Leana you did most.

00:18:13: What do you think was a project initially met with enthusiasm or skepticism from the NICUs?

00:18:21: I think it was enthusiasm because they already had The pilot project, which is no talks about so However.

00:18:29: I think the only difficulty wasn't needs to get them started again Because then To get him started again and to get all the meetings Plans and books.

00:18:43: And I think it was also difficult to select which drugs to do because we had limited time and It takes a lot of time.

00:18:53: Do you do one drug?

00:18:56: We had a really big goal of sixty trucks, so with strokes to do Which are important and what's also achievable in this timeframe.

00:19:07: So i think Maybe they were skeptical about the amount that we're going to do, but I think there would not be skeptical of what our plan was because they already experienced in a pilot project.

00:19:22: it could also help them eventually.

00:19:31: For me, one of the most striking findings during the pre-adjet period was enormous variability in local dosing protocols between NICUs.

00:19:40: So I also experienced it Germany if i talk to colleagues who put this your dozing and always surprised that they worked at three different hospitals And I saw a few different dosing regimes and Robert is a pharmacist prize by how different the recommendations were for that same drug and indication.

00:20:01: or did you expect it?

00:20:07: When I didn't know before, i didn't expected.

00:20:10: So I was surprised as well.

00:20:12: but together with Sinau I studied this kind of topics in their creation between the NICUs at an earlier stage aswell And It is a result limited evidence.

00:20:26: where translate that limited evidence, not just in one way.

00:20:33: It's also how confident you are and also with a background for example in pharmacology to understand why something is found as the result of the pharmacokinetic profile.

00:20:44: so how do drugs metabolize them?

00:20:46: Eliminate it!

00:20:48: You can relate this to kidney function a safe idea to also use the most pre-temporary infants because you are aware, from other drugs how the kidney function matures.

00:21:02: So it depends in that case on individual expertise which is locally available and when one of the doctors or pharmacist needs to approve as well feels confidence than drug B for a certain indication.

00:21:26: Yeah, then that is the practice in that NICU up till the moment when you bring all the knowledge together and you have a national consensus on what the drug or dosage would be.

00:21:38: so I think thats logical And also something which still recognises countries where they don't have this consensus.

00:21:52: So Sino from a clinical point of view, which dosing discrepancy shocked you the most during your

00:21:59: project?

00:22:01: There are many.

00:22:05: But I think with lack knowledge and if we just don't know it's not that strange there is differences right then i think theres many beliefs in every center.

00:22:15: what works or doesn't work.

00:22:16: thats also the same for probably certain dosings.

00:22:22: to probably highly believe that's the correct one, right?

00:22:24: So I think One of The Drugs That i'm Currently Really Impressed By Is The Correct Dose Of Phosphonatal Dexamethasone.

00:22:36: If I Just Think About What'S An Important Drug In The Anatology I really Believe.

00:22:41: The Dexamatazone is One Of The Savers Of Drugs Which Saves Baby.

00:22:45: in My Unit These Are Cues Them From Ventilators And Prevent Them From Beeping.

00:22:50: And Then When You Dive Into It there's no knowledge on.

00:22:53: the PK of Dextrema is unavailable.

00:22:56: No, we just know that it's metabolized by CP-III IV.

00:23:00: so we understand how the drug probably works with increasing postnatal age.

00:23:06: We don't know their correct target.

00:23:08: So this such a lack of knowledge for such an important drug I'm really impressed By.

00:23:14: How is that possible?

00:23:15: Why didn't anyone ever thought about taking some samples and make a model Dexamethasone which is probably a very important drug to us, right?

00:23:24: So

00:23:26: every

00:23:26: day we again encounter another acknowledged gap.

00:23:29: that needs to be impressive.

00:23:31: And so yeah there's many but this one currently on my mind and of course people are working on it from Amsterdam at the moment also think about new trial study although does suggest really lack of knowledge though its such an.

00:23:46: That's interesting.

00:23:48: I wouldn't have thought about dexamethasone, because there are so many clinical trials looking at dexamatazone using different dosages but i fully agree that there is no pk.

00:23:59: The same

00:24:00: for better metasone as anti-inflammatory.

00:24:03: Yeah yeah!

00:24:04: A lot of trials all use the same dose right?

00:24:08: So this if you had an open eye to death.

00:24:12: we study a lot very often just repeat what we already did.

00:24:17: That's really going back to the basics of okay, what is a target?

00:24:20: What are we aiming for.

00:24:22: Do you have a pk-target and do we understand that it's going on For most of the drugs we're using?

00:24:28: We don't have a clue.

00:24:30: It's interesting yeah...that's very important.

00:24:33: And so..do you think or other way around?

00:24:40: You've shown more than half of the consensus based dosing recommendations had to be modified after reviewing the literature.

00:24:48: So up until now, most of this content space and why is it so difficult for new evidence?

00:24:54: To change clinical practice.

00:24:56: as you already said they're using it in the longer I use a more confident iron And so i do not question that!

00:25:04: That's why nobody's looking at the literature.

00:25:06: but Why has it become so difficult?

00:25:09: Maybe Liana have an impression.

00:25:15: I think it's a difficult question, but this is also the questions that are fair to ask.

00:25:21: First what you said.

00:25:23: of course there was always loads of publications everywhere and i think its difficult even for me as researcher within projects to keep all up-to date on what has been published limited data, such as for dexamethasone.

00:25:45: For example there are a lot of studies but maybe limited from genetic data.

00:25:51: then it's also difficult to look at the data and everyone has different view on using this type of limited data And I think that is a lot work to combine all these data.

00:26:14: I tried for vancomycin, and for vanco-mycin.

00:26:18: there's a lot of data available especially a lot population pkdata And everyone suggests something different.

00:26:26: A different model.

00:26:29: However they all almost Make no conclusion at the end from what we should do.

00:26:35: now.

00:26:36: They say like yeah We made a model that's nice!

00:26:39: Then they move on which makes it quite complex to compare all the literature, but also to get a hand of what happens now and what is actually state as of the literature.

00:26:55: And does it impact for those eventually?

00:26:59: It's nice that we know their efficacy in safety with eventually for doctors or patients who need a dose that's optimal.

00:27:08: so I think this makes quite difficult.

00:27:15: That reminds me very much on resuscitation, discussion and resuscitization guidelines.

00:27:21: So I'm very much involved in this one.

00:27:23: so we have several studies on sustained inflation or optimum pressure but nobody can agree what is a translation to clinical practice now because if you change your focus then it's more important for preterm or term.

00:27:41: very similar situation.

00:27:42: So you have some evidence, it's limited evidence and then you have to make a decision on what do you recommend?

00:27:50: And Robert how did... How did your decide if you had some limited evidence but you want to make recommendation so that you can do some consensus?

00:28:03: or how did you decided what to recommend?

00:28:08: yeah optimally visualize what evidence is there, and then agree on the several aspects.

00:28:17: Because as Sena Olsja also said it would be best if you have a pharmacokinetic model to also know What the actual target in your population will be for that drug?

00:28:30: So Vancomyzen as Leonel mentioned we just used the target That has been studied in adults because there was enough data and studying to say okay We aim forward.

00:28:41: area under the curve between four and six hundred has never been studied in neonates or preterms.

00:28:49: So once we agree on that aspect, we can say okay how do you translate the functionary model to a dose such for specific ages gestational age postnatal age?

00:29:03: Then it should also agree on the safety where there's often very limited data.

00:29:09: so It is a very structured discussion on the several topics, where there's least evidence are often difficult because you need to agree what you're going to use as targets or model if you have several models.

00:29:34: Because always data that was presented in study.

00:29:41: So you also need to look, did they use the correct cohort that is representative for... ...the population where I want to get a dose of recommendation.

00:29:55: The process it's very structured using structured forms and subjects we address And very nicely prepared by Diana and colleagues.

00:30:09: Then discussion there with the consensus as a name and that can take more time if data is more variable or even limited.

00:30:26: I think, best thing about this where there's limited evidence for discussion you have all of experts on the table.

00:30:36: she mentioned at beginning Mario I'm a pharmacist with very.

00:30:40: I'm very passionate for this topic, but i am one of the few.

00:30:44: So therefore it...I always experience to be very valuable To bring my expertise thinking from The drug and combine It with all the Expertise that Sina For example has Thinking From a patient And he's an exceptional doctor because He also Has the pharmacological knowledge.

00:31:01: But That is where its most Valuable to Bring it together.

00:31:07: Then they have A good discussion.

00:31:10: I

00:31:13: mean, that's actually a very cumbersome way to generate evidence or summarize evidence.

00:31:20: But it is really necessary to bring in all these different perspectives.

00:31:26: Sino do you see any other chances?

00:31:29: how we can shorten the gap between scientific discovery and bedside implementation?

00:31:41: I'm very hopeful because you know there's so much literature coming out and i really hope that we get better tools to analyze this right.

00:31:50: So, really hopeful that AI is going help us do this for instance right?

00:31:55: When you think about doing a systematic review or reviewing all the knowledge on a certain drug it took a lot of time!

00:32:02: And...so..I am really hopeful.

00:32:10: Getting the knowledge to clinical practice is interesting, right?

00:32:12: So we realized that when one something established in their children's formulary, doctors started using it.

00:32:19: But we also found for very commonly used drugs like ibuprofen but also for instance for caffeine after a large fantastic randomized control files pharmacological knowledge gained afterwards.

00:32:33: so for instance that with social age, the clearance of caffeine is going to change.

00:32:41: And then we weren't able to convince clinicians to increase the caffeine dose at this age because everyone believes in clinical trial which has a higher level of evidence.

00:32:54: and it's exactly the same fiber-profen.

00:32:56: Everyone uses ten five milligrams for ten years to convince people you should increase by twenty or ten if your baby is older.

00:33:06: pharmacologically it's clear, but also on the level of evidence and in well if a clinical trial shows that especially long-term outcome when certain drug works we're going to use this way.

00:33:18: It was studied at trial then its very difficult to change.

00:33:24: I'm really hopeful with knowledge translation from all studies are done because there is quite some knowledge out That takes an effort.

00:33:32: to summarize I'm hopeful that we can improve the process by the help of AI tools hopefully in their very near future.

00:33:46: So, i think all neonatologists can agree that newborns cannot simply receive scaled down adult doses.

00:33:54: but as you already said We have different other factors impacting the dosing regime like postnatal age gestational age and so on.

00:34:04: Okay, can you give a very short not physiological lecture but just the very short summary which factors are or have an impact on the dosing regime like maturation and so I don't know robot or you know

00:34:25: Sure.

00:34:26: How's that?

00:34:28: The most common aspects that describe the matrational profile are gestational age for the intrauterine maturation And separately from that you have the maturation of birth, best reflected by postnatal age.

00:34:47: That's where the impact also on the development organ function enzyme activity is reflected and sometimes these are combined in a postmastral age.

00:35:02: but I think we lose quite some information there because it's better to separate gestational and post-natal but also aspects like small for gestational age, which are if we study it that has an impact on the pharmacokinetic profile in infants.

00:35:25: Also body cooling so there is multiple aspects have influence of physiological activity and each drug has its own unique Profile in how it's metabolized.

00:35:38: How its excreted and so is not just one answer for all drugs.

00:35:43: we need to logically think from the profile of the drug, how It may be impacted?

00:35:48: And study this to confirm whether We really see This and recognize this in that they are the preterm boy infants.

00:35:57: So Liana how did you kind of How did you have these under a recommendation or considered in the recommendations, different impacts?

00:36:14: We consider this mainly looking at the pharmacokinetics of the spiritual drug that we studied and taking into account what Robert said.

00:36:25: So how is it drunk this drug profile, so how is it metabolized?

00:36:30: How's the excreted and a knowledge that we have of the physiological development in term of preterm units.

00:36:39: So for example we know that the kidney function is reduced at birth and increases fast during the postnatal age.

00:36:48: uh...so

00:36:50: when a drug gets excretive you should take that into account.

00:36:53: For example, renaline of course are excluded and so that are things we considered.

00:37:02: And if for some drugs this is really relevant, then thats why we took it specifically into account with the other data

00:37:17: most often need a good loading dose, because of the different volume distribution.

00:37:31: So where we were always very careful in giving you small drugs to start with... You should probably give a lot more than that and then afterwards when the volume is large so it's relatively high levels at first but later on maybe takes longer to get rid because of this low gain function, because the liver is immature.

00:37:59: So you should load but then be careful right?

00:38:01: This a general concept.

00:38:04: that's very often how it works and That something we now know by doing all these PK studies.

00:38:11: And thats what we try to translate into those straight lines.

00:38:15: I have never thought about it.

00:38:17: But volume... Of course its more water in the preterm baby.

00:38:24: Garmel Allerhard always says that they are like jellyfish, right?

00:38:27: Like it's

00:38:27: almost

00:38:28: only water.

00:38:28: So if you have a water-soluble drug You need a lot to have certain concentration in the water Right.

00:38:35: so is there way of thinking you needed to understand what this needs to get an appropriate concentration?

00:38:41: Yeah If we're talking to our colleagues who treat adult patients They're always laughing at us That kind of calculating for body weight or so on.

00:38:52: or a pediatric patient, or pediatric colleagues.

00:38:55: They are laughing at neonatologists because they consider the postnatal age and so on.

00:39:00: Do you have an example where just downscaling paediatric dosing would be very dangerous for newborn?

00:39:10: There there is I think different types of drugs.

00:39:14: if type-of drug like an analgesic way gives to drug And you see an immediate effect that you can evaluate and may, uh, See if he needs to increase the dosage.

00:39:25: But drugs that don't show their effects immediately need a few days like antibiotics.

00:39:31: You don't want those too low because then we made in the end not treat the infected baby correctly which maybe much higher risk.

00:39:39: for Yeah there are fewer outcome.

00:39:44: So produce drugs it's.

00:39:48: It should be very well thought what dosage to use and prevent under exposure, which may also lead resistance of the drug for long future that baby still has in his or

00:40:03: her life.

00:40:07: calculate from adults or because they're like really impaired right?

00:40:11: So, yeah.

00:40:12: They don't have kidneys that work there's a different body composition so they are just the different kind of patient that requires really specific dosing.

00:40:24: There is one drug like acyclovir which is very interesting because higher dose it needed in order to prevent any other treatment but we are not knowing the dose which is optimal.

00:40:37: So, we're kind of accepting too high doses in order to prevent under-treatment.

00:40:44: so how do you deal with these?

00:40:46: because Ciclovia has also some potential side effects?

00:40:50: But how did it deal?

00:40:53: difficult

00:41:00: case indeed for acetylpher as we had previously in the pediatric formulary higher dose, for term neonates.

00:41:10: As it was based on a BOPPK model and we know that acetyltpher is routinely excreted so from there is no therapeutic target, at least we don't know it's quite the target to get with the effect and known effect.

00:41:38: And of course you don't want on a treat.

00:41:42: so that was quite difficult.

00:41:44: also found limited safety data available which makes Dutch Peter The greatest is that it's quite dynamic, so as an advantage just means if there are changes in evidence or we can look at the representation of the evidence now and see for those should change.

00:42:08: So from then we changed a little bit lower dose which was used with other age groups because There was the literature that we had based on those run-on, it wasn't representative anymore and there were better research out there.

00:42:36: And there also limited safety data.

00:42:40: so with a higher dose you could not defend such high doses Lower those that was a fixie data.

00:42:50: So we know, right?

00:42:55: We would not on the tree.

00:42:56: so therefore which decided to Change it back again through the old dose that we had in the pediatric formulary.

00:43:05: But yeah there are some changes too.

00:43:07: if you have some decisions To be made of course when you want to implement Changes or go back to your oldest And I think is good to have the experts on board and to have opinions of this.

00:43:25: And also, see how good is evidence that we use?

00:43:31: If I may add for acyclovir it was challenging because there's a lack of knowledge but if a baby suffers and needs an adequate dose you don't take risk.

00:43:43: Well, we didn't

00:43:50: think that

00:43:51: it was a real risk-benefit analysis and we thought the risks is just too high in relatively lack of knowledge area to decide.

00:43:59: Just lower those taking a risk for another treatment that outweighs potential risk for side effects because you're probably going lose your baby if you dose it inadequately.

00:44:12: so I don't think this was an interesting discussion indeed.

00:44:19: So, you know for clinicians listening to the podcast.

00:44:22: How should near those recommendations actually be used as a bedside?

00:44:28: Just use them right?

00:44:30: No I fail.

00:44:31: so we try to have.

00:44:33: We tried to make close recommendation that are feasible for clinical practice or we always discuss And sometimes every day can be complicated dosing regimen our recommendation for certain drugs.

00:44:46: We always try to keep them simple and feasible for clinical practice.

00:44:50: And hopefully there are, but of course this should be interaction.

00:44:54: so if stuff doesn't work or... If they're still doses that are missing Or you using a drug in certain population That's not advised yet.

00:45:04: The feedback is really important because we need further improvement probably To keep it updated etc.

00:45:10: So I hope its useful for clinicians although it's a pity that is not available for everyone around the world, so there are some things still to think and work on.

00:45:21: Because I think its really valuable.

00:45:24: if you're busy in clinical practice your gonna need a drug which isn't commonly used using or prescribing.

00:45:32: You can just search a certain page where there is an adequate dosing advice That instantly helps you provide a theoretical dose.

00:45:42: So what is a problem?

00:45:43: why it's not available around

00:45:44: the world?

00:45:48: It's work in progress to me.

00:45:52: I'm not really involved because this has done by children from an area itself and then team there, um... ...I think its just open for further federalization around Europe and the worlds.

00:46:08: But it also took a lot of money and effort.

00:46:10: And so, It's not the commercial company or whatsoever but The work needs to be paid.

00:46:23: So I think its open As far as i know To talk about collaborate the cheaper it gets, right?

00:46:31: So I think hopefully work in progress to have this available.

00:46:35: But every country has its own specific adaptations that are needed and so there takes a bit of or not a bit probably quite some additional works... Hopefully this is working for

00:46:51: us.

00:46:56: Indeed, there are some examples that have already succeeded with Germany, Austria and Norway in collaboration.

00:47:08: Maybe it's good to mention that it is free-assessable at least via the form.

00:47:13: Of course you should be able read one of the languages which makes things a little bit more complicated but I think It is free accessible.

00:47:28: Okay, so we will have a link for this one as well.

00:47:32: and just the final question.

00:47:34: So We Have Already Discussed About The Adherence To The All Prescription System Because You Are Used to it And Now Its One Thing To Publish Evidence Based Recommendation But Another To Change Daily Prescribing Behavior From Everybody.

00:47:51: Just A Very Short Answer What is the most important aspect in introducing these evidence-based recommendations into clinical routine, Robert?

00:48:05: In the Netherlands we are very happy that it's really a formal source for prescribers to find their dosing information.

00:48:11: So its very formally adapted and integrated with national drug database from the National Pharmacists.

00:48:21: We integrate pediatric doses there as well.

00:48:25: So also our electronic prescribers directly get feedback if they have an incorrect dosage or a contraindication, or interaction with another drug that the patient gets.

00:48:35: It's really completely integrated in our system.

00:48:40: Viana from your perspective?

00:48:45: From my perspective I think it is collaboration that needs to be happening between all resources and fields.

00:48:56: I think this podcast helps everyone to be aware on that.

00:48:59: This is needed and then you should just use the evidence of knowledge sets out there, right?

00:49:04: So i think this why we are doing it like to

00:49:07: answer was expecting yes thank you okay so my final question always asked a more general question what advice would give young me an autologist fellows or researchers who want contribute innovation Maybe neonatal pharmacology or neonatology in general.

00:49:29: So what is your experience,

00:49:31: Leana?

00:49:33: I think for me it's just a start and not to be afraid!

00:49:39: To check with the neonatologists who are already in practice... ...what their gaps are and discover areas that are overlooked which are not sexy but definitely needed to make an impact.

00:49:56: Okay, Robert what is your suggestion?

00:50:00: right?

00:50:00: twice?

00:50:03: To encourage whether you're a pharmacist or physician... ...to really find the other expertise.

00:50:10: so if you are standing and working in the clinic.. ..you have a question on drugs.

00:50:15: where you cannot find a drug with good feeling then you should contact the pharmacists involve others directly around you to think what is well in that case will be the best drug to use and Best dosage to use.

00:50:29: so more Collaboration

00:50:34: Sino.

00:50:35: Yeah, it's a. for me It's really important to realize that all these young doctors study medicine right?

00:50:40: So you studied medicine But you don't understand medicines And I think something to open your mind.

00:50:46: then just ask questions Asked questions through consultants to the neonatologists to nurses.

00:50:52: everyone was using drugs.

00:50:53: Do they understand how the drugs works?

00:50:55: Are you sure on a dose,

00:50:56: etc.?

00:50:57: And so then hopefully get really interested and fascinated by all this knowledge that is around.

00:51:04: Hopefully also are motivated to help us to get these fields forward.

00:51:13: That's good point!

00:51:14: We studied medicine but we don't know medicines very well... Thank you very much.

00:51:20: So today's conversation highlighted how neonatal pharmacotherapy is evolving from tradition-based prescribing to truly evidence based and individualized care, And the NEODOS project demonstrates what it possible when Neonatologist, Pharmacist & Researcher collaborate nationally To improve outcomes for preterm babies?

00:51:42: I really thank my guests Robert Liane Sino for joining us and sharing your insights, experience.

00:51:52: And thank you very much to our listeners!

00:51:53: If you enjoyed this episode please subscribe share it with colleagues that join us next time

00:51:59: as we continue

00:52:00: exploring the future of neonatal medicine.

00:52:03: Thank You to my guests!

00:52:05: That was it again!

00:52:08: Neonatology know – The podcast of the European School Of Neonanatology.

00:52:14: Marie-Rudy on the mic & My Guests For Today were Liane Brassels Sino Simmons and

00:52:19: Robert Flint

00:52:20: from the Netherlands.

00:52:22: If you do have any questions or comments, don't hesitate to contact us!

00:52:26: Thank You for listening.