Hello, everyone. So similar to the previous speakers before me, I'm going to be talking a little bit about the challenges of caring for the critically ill patient with severe obesity and focusing a little bit on the adjustments in pharmacotherapy. Kind of full disclosure, I'm not going to be able to give you an exact regimen for every single patient that you look at, but we'll walk through some things to consider as well as some thought processes that would be helpful when considering adjustments in pharmacotherapy. So this is a brief introduction for me, but I do have nothing to disclose for this presentation. And our lecture outline today is to start by talking about some pharmacokinetic alterations and kind of implications within this population that we might see, as well as then that will kind of lead us to introducing either those pharmacotherapy targets or the medication of interest or what we want to look at, maybe when we're looking at a medication's either package insert or we're looking at literature. Bring up some challenges when it comes to kind of doing that research and trying to find that right adjustment in pharmacotherapy, and then also kind of talk about some research or outcomes of interest that we might be targeting kind of within those challenges that we face. We'll go through a brief evidence summary, kind of focusing on common medications that we're using within the ICU, and then we'll kind of finish by walking through a clinical approach to this patient population and kind of an overarching kind of approach to kind of personalizing their adjustments in pharmacotherapy. So to start off, we'll talk about those pharmacokinetic alterations. So you have on this slide a table that attempts to differentiate the alterations that we might see within the critically ill patient and also the alterations we might see within the critically ill patient with severe obesity. So for the pharmacokinetic changes that we'd see are absorption, distribution, metabolism, and the distribution involves not only the volume and distribution of the drug as well as the changes in plasma protein binding that we can see. Primarily when we're talking about metabolism, we're talking about hepatic metabolism. And then finally, our final piece of the ADME process of excretion is typically again talking about renal excretion. And I'll just disclose that a patient, everyone knows when you see a patient in the ICU, they don't always follow certain trends when it comes to these pharmacokinetic alterations. But I've kind of put here some trends that we might see. So for absorption with a critically ill population, sometimes you can see a decrease in both enteral and sub-q absorption. And as far as the literature is concerned, that's likely going to be potentially similar within the severely obese population. When it comes to distribution, we often see an overall increase in the volume and distribution, whether that is related to fluid resuscitation or kind of other disease states that we manage, as well as an increase in unbrowned or free drug. That is something that we see within the trends of a critically ill severe obese population as well. And that actually might be a situation where you have a larger volume and distribution that you're potentially trying to overcome. With hepatic metabolism, oftentimes we might, that's overall potentially not different in a critically ill or a critically ill severely obese patient. But that can be decreased. And from the literature, we don't really see huge differences there. And then finally, excretion is an ICU practitioner. You might see primarily renal. You see increases in renal excretion, decreases in renal excretion, or relatively no changes because we have some non-renal clearance that happens out there for certain medications. That's also an area within the literature that you might have an enhanced renal excretion of a drug in a severely obese patient population. So now that we know those pharmacokinetic alterations and those trends, how does that identify what medications might be of interest to us and what pharmacotherapy might be of interest to us to adjust? And so isolating those two alterations in volume and distribution, so thinking about volume and distribution, breaking it down a little bit further into knowing whether or not your medication is a hydrophilic versus a lipophilic drug is important. Knowing where it distributes, whether that be in the blood volume versus adipose tissue and what that actually means. And then kind of moving on to the excretion piece of it, likely you're going to see at least in a calculated creatinine clearance for MAP, something that looks like augmented renal clearance because we are capturing really estimations when it comes to that glomerular filtration rate. But knowing what that medication's renal as well as non-renal clearance might help you to come up with a specific plan for that patient. So kind of moving on from the pharmacokinetic changes that we see onto some of those challenges. So it's not just as simple as looking this up in Micromedics and looking at the label or, you know, whatever tertiary research you use and looking at the dosing kind of literature that we have here. A recent colleague described that only a third, roughly a third of our ICU medications actually describe the weight in the dosing. And oftentimes some of those traditional weight metrics don't necessarily account for those changes in body composition for a variety of maybe calculated BMIs, which we kind of talked about previously. So there are some standard kind of weight metrics that are referenced. On this slide you can see total body weight, lean body weight, ideal body weight, and adjusted body weight that we often, that have standards for calculations and also can be referenced kind of within some of those tertiary researches that we're looking at. And so I put these there for you all as well because I'll kind of refer to those as we go through our evidence summary. And then finally, while we have like kind of a dearth of this information available, we kind of have to balance that, right, because we know that dose optimization does matter. So our goals in this situation are to minimize that treatment failure while also kind of avoiding those issues with adverse effects. So kind of delving a little bit deeper about the labeling issues that we kind of face when we're looking at some of these challenges, again, one of our colleagues recently kind of described these things. Here's a list of some of the labeling kind of things that we have for certain medications. Some of the issues that we see with that is that they're fairly like very open in terms of exactly what you need to do in terms of reducing the dose or it may need modification. And then when it comes to kind of delving a little bit deeper into the population or the evidence behind that, we rarely see things like a couple examples here where it breaks down the patients that were included according to obesity and severe obesity. And then also, we oftentimes will not see some of the details here that you can see for rocuronium, like how many patients were included, and some of those outcomes that are things to consider as well. All right. So now that we've established a little bit about those challenges, so it's not as simple as kind of looking at a labeling kind of thing to figure out what you need to do. When we're talking about this balance of treatment failure with adverse effects, oftentimes with our efficacy, the outcomes of interest for us are oftentimes going to be therapeutic drug monitoring, whether or not that is the concentration of the medication within the body or whether or not that's the pharmacodynamic effect. So there may be labs that are associated with measuring their actual pharmacodynamic effect. One example for you here is the use of, for antimicrobials, oftentimes there are specific target attainments that you might see that are related to the kind of the killing effect of that particular antimicrobial. So those are some things to keep in mind. And then kind of on the other side of reducing adverse effects, some of those things that you would want to see if you're looking into the literature, whether or not you're able to minimize this risk of overexposure. So for example, when we're looking at anticoagulants, whether or not that actually kind of results in a decrease in bleeding incidence. All right, so I'm delving down a little bit into our evidence summary. And just a disclosure, again, this is not every single information out there. This is kind of just going over some common things that we see. When it comes to antimicrobials, there's actually a lot of information out there for you guys to review. And I focused today on beta-lactams, mostly because the literature that I compiled on this slide had at least over 500 patients with obesity that were included kind of amongst these studies. There's generally, they usually cover cephalosporins. There's a little bit more medication-specific literature with cefazolin and cefepime, meropenem, and piperacillin-tazobactam. So some of the outcomes we are seeing, unfortunately, is with this population, some higher rates of treatment failure, as well as longer hospitalizations. We've also found a recent study that noted that obesity was a risk factor for neurotoxicity associated with cefepime. While these findings still bring out a lot of questions for what to exactly do in this population, some conclusions that we can come to is that for beta-lactams in particular, if you guys are familiar, the optimal free time above the MIC is what we're looking for. And so for this kind of situation in general, the minimum exposure would be 40% to 100% of the free time above the MIC, which generally you all can achieve by either looking at a dose that has been used in a similar population that would do that, or fortunately for me at my institution, I go straight to therapeutic drug monitoring, and I have that available to me usually the next day. So this can tell us that there's also a role for therapeutic drug monitoring for efficacy and then also potentially for safety as well. So exactly what thresholds do we need to potentially worry about this neurotoxicity in, and that's still kind of yet to come, but really showing the kind of interesting kind of differences and discrepancies there. So moving on to another common agent that we utilize within the ICU, so our anticoagulants, and really just focusing on enoxaparin and heparin for now. Most of the outcomes that we see within literature are related to anticoagulation assays, but fortunately we do see some literature that talks about kind of more of those clinical outcomes such as the race of venous thromboembolism. So kind of two things that I'll be addressing when it comes to the findings and conclusions are using these agents both for VTE prophylaxis as well as kind of therapeutic administration. So when it comes to prophylaxis in general, the term, again, I'm going to be similar to my labeling out there and say that you typically would need a higher dose. There is some literature to support that heparin may not need to be adjusted until the BMI is greater than or equal to 50. However, I think not all patients are created equal, and so I think, again, being individualized, doing a risk-benefit ratio for that patient would be important. There's recommended no-dose capping for weight-based doses for enoxaparin, and then there's a slight preference towards adjusted body weight dosing with no capping for patients that are being provided therapeutic intravenous unfractionated heparin dosing. All right, finally, the next kind of, it's not really a class of drugs, but it is a thing that we commonly do in the ICU is titrate our medications to their clinical effect. So I've included here a couple of classes of things that are titratable to the effect. When it comes to hemodynamic support, specifically our vasopressors, there's a variety of things that you would see in literature, but I think the outcomes, though, is that there is some interpatient variability and response, depending on what kind of dose regimen that you utilize. And then the conclusions you can make from that are to generally be consistent at your interstitutions to help to minimize the error. So either you utilize non-weight-based administration of vasopressors, or you use the same weight for all those patients, so ideal body weight or adjusted body weight would be the recommendations as far as that's concerned. When it comes to analgesics and sedatives, there are a lot of drugs within those classes, but oftentimes the outcomes that we see are just that these have a prolonged half-life within this population and maybe would have unpredictable awakening times. I think the reason for this and some of those conclusions from that is that most of those medications have some degree of lipophilicity, and their dose on actually should be total body weight. I've also used actual body weight there. But I think from a conclusion standpoint, it may or may not have an unpredictable awakening time, depending on the length of the therapy, and so that should probably be taken into account as well. All right, so coming up with that, taking all the evidence that we've talked to and coming up with a clinical approach to those adjustments in pharmacotherapy, I think we've been able to emphasize that there is some monitoring involved, and hopefully we're able to do things that are specific to that patient and the disease state that we're trying to treat. And although the therapeutic drug monitoring that we see would vary based on medication as well as those different targets that we might be having, when it comes to initial dosing regimen, having to weigh those benefits and risk, and depending on the medication that you might be dosing, thinking about whether or not that drug has a narrow or wide therapeutic drug index. So for instance, erring on the higher side of dosing potentially when it's known that they have a low incidence of side effects with that higher dosing or adverse events with those higher dosing, but maybe not being as aggressive with that first dose when we're talking about our narrow therapeutic drug index. The other thing I wanted to kind of address is when you're looking at that literature, and you're doing that, and you're trying to come up with your plan for your adjustments in pharmacotherapy, kind of try to figure out if you can specify the data was in the patients with obesity versus patients with severe obesity, because oftentimes you'll find they're often lumped together because we don't have a ton of evidence out there, and it's just kind of interesting to look further to see if those kind of trends within the outcomes that we see would be kind of equivalent in those populations as well. So in summary, when it comes to our adjustments in pharmacotherapy in this population, our pharmacokinetic changes for critically ill, severely obese patients largely follow our trends for critical illness. We do potentially see some larger changes when it comes to volume and distribution, as well as the idea of augmented renal clearance. With the limited preclinical evidence that we have and the challenges that we have with the labeling, it's really important to come up with a personalized approach to dosing within this population. The evidence that can be prevented today supports a couple of trends and some pearls to support your initial dosing, but it also supports making sure when we can that we're using clinical monitoring with an emphasis on kind of monitoring those medications with a narrow therapeutic drug index or those that have kind of a higher stakes scenario. Thank you for listening to the talk.

severe obesity

pharmacokinetic alterations

medication dosing

ICU medications

individualized dosing