Thank you, everyone. It's my honor to be here today. My name is Brittany Bissell Turpin. I am an advanced clinical pharmacist coming out of Kentucky. It is my honor to represent our task force, looking specifically at norepinephrine challenges and as it pertains to the critical care community. So for myself, I have no disclosures as it pertains to this presentation, and I personally just have one sole objective today, and that is to talk through current challenges with norepinephrine concentration variability. Specifically, this is discussing how we report norepinephrine concentrations and how we take these considerations into our practice, especially looking at a multicenter and a multinational level. So this task force was developed in the latter half of 2023 based on some recognition and awareness of a group of different individuals. Some appear with me today and some not up on the stage, but really just a number of clinicians that started to develop or become aware of potentially inconsistent reports of norepinephrine and how we report norepinephrine concentrations in our literature. And so you'll see here a couple of those key papers that have been published in the last year or so, and I want to call direct attention to Dr. Leon's publication and then that of Dr. Viroshefsky that really looked deeper into what we're seeing from a clinical standpoint in the reporting of norepinephrine doses. So let's talk a little bit more about what I'm really leaning into here. So this was our position paper that was published earlier this week. Please take some time to look at it. I have to call attention to this group of authors. It has been a huge honor to be able to work with definitely the most efficient group of authors that I've ever been a part of and just an amazing team and super effective. And Dr. Khanna was able to grab everyone's headshot to show, I'll just bring a little bit of attention to the group here. I'm not sure if everyone wants this to be up there, but nonetheless, just an amazing group of authors with so much insight from so many different practice backgrounds, an amazing group of educators, clinicians, researchers. It's really been my honor. So let's get into it. From a pharmacology standpoint, norepinephrine, as well as many other drugs, is available via a salt formulation. We refer to the drugs that we most commonly think of as APIs or active pharmaceutical ingredients. So when we talk about norepinephrine or epinephrine or vancomycin, we're really referring to the drug. And that's what we're thinking about as clinicians when we're applying these medicines to our patients at bedside. Unfortunately or fortunately, we must require salt formulations for about 50% of all medicinal agents, 70% of intravenous agents in order to actually administer these medications safely to our patients. This is dependent on a number of different factors, whether it be the chemistry of the actual agent or pharmacokinetic or pharmacodynamic expectations or other factors. And so norepinephrine is one of those agents. So norepinephrine's salt formulation or the conjugated salt form allows us to administer this medication intravenously. And this is because of the underlying low water solubility of the medication. So what does this mean? Not a lot in direct practice. Not a lot of attention is probably paid attention or called to or called for when we talk about the salt formulations and whether we're using one versus the other. But this may have some implications in reporting. And so there's three key salt formulations that we have with norepinephrine. We have norepinephrine bitartrate, we have norepinephrine tartrate, and norepinephrine hydrochloride, also known as noradrenaline to our European and other colleagues. In the United States, we heavily focus on the use of norepinephrine bitartrate, whereas in European countries, we see the tartrate formulation. And in some countries, such as Germany and Austria, we see the utilization of the hydrochloride salt. Now, the weight is obviously much different with a salt formulation, as those agents are then heavier than maybe just the active pharmaceutical ingredient. We see a two-to-one ratio, essentially, with our bitartrate and tartrate formulations, and we'll focus on that for the majority of the presentation. So again, from a pharmacology standpoint, not a huge impact in which salt formulation we use with the slightly different isomer and that water molecule that we see there. So not a huge consideration in our active everyday practice of what salt formulation we're applying to patients at bedside. Where we do need to start considering the implications of salt formulation comes in our labeling and reporting. So the salt formulation or base concentration and what is reported in labeling is really dependent both on the manufacturer as well as the country. We know that about half of intensivists reported in a survey that they're unaware of the salt formulation that is given in their intensive care unit or their critical care unit. And I think that's pretty true for most of us. We're not looking for what salt we're actively administering every day, which, again, may not have a lot of direct implications to our patient care at bedside. But it is important when we talk about how we report these doses across different institutions and across different countries. In the United States, we typically discuss norepinephrine exposure on the basis of the API or the base concentration, so that one milligram of norepinephrine. However, some of our colleagues in Europe and elsewhere may report either the base or the salt formulation. So you may see a two or a one milligram per ml concentration depending on where you're at. And Dr. Viresky actually looked at a review of 32 different countries and really helped us start this task force with his work looking into the different prescribing informations that were available worldwide. And in his review of 32 different countries, he found that prescribing information consistently, as expected, does include your salt formulation and also includes the base concentration. Where things start to differ is when it comes to the active drug label, with four countries actually listing the salt formulation as the concentration on the label. So a difference than you would see from the base concentration. Interestingly enough, two manufacturers specifically would label their drugs on the basis of the country that they were supplying to. So not even necessarily consistency within the direct manufacturing process or their labeling process and techniques. So what does this look like at bedside? We have here an example. So you have prescribing information as listed here with a highlight on the bottom that is going to report exactly what is expected and what you see in that medication. So you have a base concentration on the left of one milligram per ml, which is what is represented on the label. However, if you were to have an agent that reports specifically the salt concentration on the label as there to the right, you're going to see the same drug concentration, but it actually represents what is 0.5 milligrams per ml of base. So half really of the dose if you compare these two agents just at face value. So if we're administering these to our patients and we have what appears to be a very similar patient population in the smart pump that we have on the left compared to the smart pump on the right, we may be administering what appears to be the exact same dose in two different patients. But when you dig further, you actually recognize that you may be administering either 50 percent or double the expected dose. And what implications does this have on the critical care community? Well, a group could think of quite a bit. I'll try to keep them short and simple here. Probably the most obvious and most prevalent are the implications for research. When we talk about enrollment, particularly in multinational multi-center studies, if you're utilizing or you have different centers that are utilizing different standards for dose reporting, you can have a lot of heterogeneity in the patient population for enrollment. If you're using enrichment procedures or you're trying to look at dose equivalency or you're trying to look at exposure ratios and overall outcomes, you may be really comparing for lack of a better term apples to oranges just within that cohort itself and not intentionally. There may be inconsistency of findings, and when we're looking at, you know, polled estimates or meta-analyses and things of that nature, we may be combining very heterogeneic populations unintentionally. And so this, of course, then translates to our clinical guidelines. We have surviving sepsis guidelines and others that specifically call for initiation or weaning of different agents based on certain vasopressor thresholds. And so, again, if we're not reporting a consistent value or utilizing a similar concentration across all cohorts, we may have some confusion in how we're implementing these agents. For prognostication, of course, whether we're using salt formulation versus base concentration as a reporting is going to make a difference. And in clinical practice, of course, the most important area, bringing all of these things into fruition for active patient care, we may have heterogeneity in our own practices, but we also may be deviating from the evidence base that we know it. So in image form, if we take, for example, enrollment procedures in a clinical trial, you'll see here on the top left, we have two different cohorts. One center, for say, that is dosing their norepinephrine based on the salt formulation, and one that's utilizing the base concentration. If we have a predefined enrollment threshold based on our underlying norepinephrine base concentration, if a center is unknowingly utilizing tartrate salt, titrate or bitartrate salt concentrations as their dosing parameter, they may end up enrolling patients much quicker than they would technically be eligible for enrollment into this clinical study. And in image B and image C, you'll see similar scenarios where, depending on how fast or slow the titration is going, you can see very different inclusion timing or parameters for these patients, depending on what center or country, et cetera, where the patient is enrolling. Worst case scenario, potentially, is our image D here, where you may potentially enroll a patient because you're reporting double the dose concentration that otherwise would have never actually met that enrollment threshold in other circumstances. So several implications in study enrollment procedures. And this is not uncommon to us, right, in the critical care arena. We know there are several trials out there that many in this room have participated in and learned from and utilized in their everyday practice that have predefined enrollment thresholds for norepinephrine exposure or norepinephrine equivalents. Some of these trials specified SOFA scores or organ failure assessment, which, again, does have influence by the norepinephrine dosing at enrollment. So if we look at prognosis and how we prognosticate our patients on the basis of catecholamine exposure, you'll see here to the right, if you're looking at a difference of the dose reported by the salt formulation versus the base concentration, you have the potential for very different predictions in mortality, considering what number or what concentration you're putting into our calculation. This amplifies even further when you have patients with other types of organ failure. Again, you have the potential for stark differences in your expected mortality in these patient populations, which is important in our clinical trials, but important at bedside and in practice as well. And, of course, some of the authors that I had mentioned earlier have tried to make efforts to look at how we prognosticate patients on the basis of catecholamine requirements. But these data become limited if we don't think through, again, our underlying concentration and what doses we're actually reporting and using to find these different predictive values. You'll see here on the bottom left the graph by Dr. Leone and colleagues that show very different dose ranges at the same expected mortality rate. So I've talked about some of these already, but, again, relevance to clinical practice is really, really present in a number of different ways. We have our organ failure assessment scores. We have the surviving sepsis guidelines that we're taking to bedside with us every single day. We also have our ECMO and extracoreal life support guidelines that also include catecholamine requirements as a potential marker for adjunctive therapies. We also have our vasopressor equivalent calculations, which some of our authors on this panel as well have made a lot of effort into trying to develop calculators and scores and able to use vasopressor equivalency in order to compare our agents, utilize these agents in a similar value or range in order to enroll patients in studies. There's a lot of effort that's been dedicated to evaluating these criteria. And what we're reporting, again, matters quite a bit when comparing these different agents. If we think through our clinical approaches at bedside and how this may actively impact what we're doing for patient care, the top image here is how we may consider weaning agents on the basis of dose reporting. So if we are a facility that is reporting our salt formulation, you're going to see here that the dose is going to remain higher as reported for a longer period of time than you would see from a base concentration. So if you're waiting to wean certain adjunctive agents, et cetera, until you hit a certain dose threshold, you're going to hit that much later if you're utilizing your salt concentration as your marker for wean of that therapy. And the opposite is then true for the initiation of adjuncts, right? So if we're waiting until we have a certain dose met before we initiate other adjunctive therapies, we're going to do so much quicker with using the salt concentration as our dosing mechanism versus what we would with base. And so potentially over-utilization of our adjunctive agents or longer duration of these adjunct agents that maybe wouldn't be seen with a more uniform dosing standard. So in conclusion, there are a few different options when it comes to our salt forms of norepinephrine. And the utilization and dose reporting can manufacture not only by the country but also by the drug manufacturer. And the impact, obviously, as I've already stated, can be seen across a number of different domains, whether that's drug operations or clinical bedside practice or research in itself. I'd be remiss if I didn't make a couple of acknowledgments. Again, it's been an honor to work with this panel. We appreciate all of the ESICM and SCCM staff and leadership that has been able to form this group and allow us to produce this work. So thank you.

norepinephrine

clinical pharmacist

dosing standards

multinational studies

patient care