Okay. So, I don't have any conflicts of interest to disclose regarding the content of this presentation. I am a consultant for Walters Kluwer. There's a lot of content that we're going to get there. We are a little bit behind. So, I'm actually going to just jump right into it. And I know that I don't have to belabor these concepts to this group because I know that we're all very aware and in tuned with the fact that when we're prescribing and administering medications, dosing matters. And we have to balance the potential medication-related toxicities that can be associated with overdosing our patients and the potential treatment failures that can be associated with underdosing our patients. Now, the population that we're focusing on today is those that are critically ill, those that develop AKI, potentially go on to need renal replacement therapy or need it at baseline. We know these patients are at risk of either of these two phenomenon occurring, overdosing and underdosing, because there is a relative lack of data guiding hard drug dosing in this patient population. It probably also isn't a surprise to us that when we're talking about critically ill patients, the vast majority, if not all of them, are going to require some type of medication dose adjustment when they go on or if they go on to develop some type of acute kidney injury or alterations in their renal function. Now, throughout my portion of the talk, we're going to interweave a patient case. So, I want to introduce this patient briefly. So, this patient is MJ, a 67-year-old male presenting to the emergency department from a skilled nursing facility, hypotensive, febrile, and with altered mentation. You could see his past medical history for you on this slide. One of the more pertinent of which is he had a stroke in 2021 that left him with residual left-sided weakness and resulting in a trach and plague, so lots of comorbid conditions going on. You could see his vital signs there as well as his pertinent lab values. He has leukocytosis as well as a hyperlactatemia with a lactate of 3.3. His UA is positive for 2 plus leukocyte esterases, 2 plus nitrates, and over 100,000 white blood cells. You can see his serum creatinine at baseline is 0.9. Now, the team initially suspects septic shock, very appropriately so. They fluid resuscitate this patient with 30 milliliters per liter per kilo of lactated ringers. Vasopressors are required to augment hemodynamics requiring a dose of norepinephrine of 10 mics per minute or 0.12 mics per kilo per minute depending on your language of dosing vasopressors, and he's initiated on broad-spectrum antibiotics with piperacillin-tazobactam. Now, I never speak brand names, but I'm going to refer to this as Zosyn throughout the talk as well as vancomycin. The question then becomes posed of, okay, you want to start these antibiotics. That's great, but how do we dose them? How do we take all of the concepts that we learned about today and then take that and apply it to our drug dosing of our patients that are going to be, one, critically ill like this patient right now, and then maybe go on to develop AKI, spoiler alert. That's what we're going to see with this patient as we move forward. Now, the things that we're going to talk about as we go through this, I feel like a lot of this is probably a review to this group, but to bring it all together into one picture, we're going to talk about a lot of patient-specific factors as well as drug-specific factors and pharmacodynamic and pharmacokinetic properties. There we go. Thank you. We're going to start with the pharmacokinetic and pharmacodynamic properties. Perfect. So, recalling when we refer to pharmacokinetics, what we're referring to is factors determining how drugs move through the body. So, thinking absorption, distribution, metabolism, elimination. On the other side, when we're thinking about and talking about pharmacodynamics, we're talking about the clinical effect of the medication, its mechanism of action, and then its actual efficacy, so how the drug affects the body. Now, these factors are extremely important when we're talking about patients who are critically ill because we have to know a couple of things. One, there's a lot of alterations in patients' pharmacokinetics that are going to then impact the ability to achieve those pharmacodynamic parameters and that efficacy that we're looking for. What we don't 100% know is whether these pharmacokinetic alterations that are impacting our ability to achieve our pharmacodynamic profiles and targets are actually impacting downstream clinical effects, but we are still going to try to overcome these pharmacokinetic alterations by optimizing our drug dosing. Now, what these alterations are, just to name a few briefly, our critically ill patients are going to have altered tissue perfusion. They're going to have altered clearance, which we're going to talk a lot about today, and they also have an altered volume of distribution. Now, what volume of distribution is what this refers to is the ratio of the drug in the body, the total amount of drug in the body by the plasma concentration. The larger the volume of distribution, the more extensively that drug is distributed into the tissues. So, the reason that this is extremely important is because that intravascular drug in space is going to be where our efficacy lies. So, in our patients who are critically ill, we see a significant increase in their volume of distribution for many different factors. These patients are massively vasodilated. They have nitric oxide release. They're getting aggressive fluid resuscitation, maybe, depending on the patient scenario. So, there's many different reasons why these patients have this enlarged volume of distribution that we have to overcome with our drug dosing. For example, with some of our antimicrobial agents, which will be the focus of the drugs that we talk about today, you can see as much as a 100% increase in the volume of distribution in our antibiotics like beta-lactams, vancomycin, as well as aminoglycosides. Now, I'm jumping ahead a little bit here, but what this looks like in somebody who's going to require dialysis, this is an important concept, because only the drug in the intravascular space is going to be removed. So, the larger of the volume of distribution, the less drug that's available to be removed through dialysis. Now, when we're talking about our pharmacodynamic properties, and specifically with our antimicrobial agents, there's three targets that we're trying to achieve, and it's going to depend on the specific antimicrobial agent. So, there are antimicrobial agents that are concentration-dependent, time-dependent, and AUC-dependent. Now, why this matters is because we need to optimize and achieve this pharmacodynamic parameter in order to optimize our bactericidal activity or our kill characteristics of our antimicrobial agents. So, our concentration-dependent antibiotics are our fluoroquinolones, aminoglycosides, metronidazole, and daptomycin. What matters here, what we're targeting here is that peak concentration, and the goal is the peak to MIC ratio. The peak concentration to the minimum inhibitory concentration of the pathogen that is isolated. So, in order to optimize this parameter, we're going to give high doses of medications. So, this is why you should see high doses of aminoglycosides given, regardless of renal function, in patients with decompensating septic shock, which is a practice that we utilize at my institution for double-gram negative coverage. Now, our time-dependent antibiotics, what matters here is that the plasma concentration, the amount of time that that specific plasma concentration is above the minimum inhibitory concentration of the pathogen. These are your beta-lactams and linazolid. And then, our AUC-dependent antibiotics, like vancomycin and macrolides, what matters is the concentration of under the area, sorry, under the concentration time curve, which is the shaded-in portion on the graph for you. Now, the way to optimize this parameter would be to give more drug more frequently. So, going back to our patient, who was administered and initiated on zosyn and vancomycin, the question is posed to us, how do we dose their antibiotics? And now, this is something that I'm hoping to provide some insight into as we continue throughout the rest of this conversation. And now, applying it to the agents that we're using right now, this patient, as you recall, has a serum creatinine of 0.9. We're going to go into what that means, breaking it down, the limitations of serum creatinine, some of which you've already heard. But right at this stage in this patient's hospitalization, I'm going to treat him like he has normal renal function, based on the information that I have already provided you, nothing more. So, again, beta-lactams are time-dependent antibiotic. The way to overcome these alterations in pharmacokinetics, the things we're working against, he was volume resuscitated, he's vasodilated, he has this massive increase in volume of distribution. It's going to be difficult to achieve that PKPD parameter of time above the MIC. To do this, I'm going to give the drug more frequently. So, a typical standard regimen for zosyn can be about 3.375 grams every four to six hours. Typically, you probably would start with every six hours. Now, I might push this and give it every four hours because of all of these things that I am working against in this scenario. So, it's probably where I would start this patient at this point in time. There's other regimens. There's going to be many that are right, many that are probably not wrong, but this would be the regimen that I would at least start with. Now, vancomycin, our AUC-dependent antibiotic, again, I'm going to dose this for normal renal function, working against all these same factors. So, in order to administer more aggressive dosing, I'm going to give higher dosing more frequently. And now, treating this patient like a normal renal function patient, but knowing I'm working against all these things, I'm going to give this patient a loading dose, which is often done in patients who are critically ill with this drug. So, it has a longer half-life, takes longer to get, time to get to steady state. So, a typical load in somebody who's critically ill will be anywhere from 20 to 25 milligrams per kilo. In this patient, it would be 2 grams, followed by a standard maintenance regimen of 15 milligrams per kilo every 12 hours. Now, 48 hours after admission to the ICU, his blood culture has popped back with Pseudomonas aeruginosa 2 of 2. His urine culture is also revealing for the same organism. Antimicrobial stewardship at its finest, let us discontinue vancomycin, continuing on zosyn. His blood pressures have, and his hemodynamics have improved, but still require 2 mics per minute of norepinephrine. But you can see his now updated laboratory values 48 hours later. That serum creatinine has increased to 1.5. Leukocytosis is improving. Lactate and hypoperfusion has improved as well. So, overall, doing well, but it looks like he's starting to develop an AKI. So, the question now is, oh my gosh, do we need to alter our dosing of our antimicrobial agents? Now, in order to answer this question, there's a lot of concepts that we need to take into account. So, this is all the things going on in my pharmacist's brain at the same time. So, the first concept that I want to break down is the concept of total body clearance. So, this is the sum of all of the clearance processes that are occurring in the different organ systems. It might sound very common sense, and it is to probably all of us in this room, but I think a lot of people forget, depending on the patient scenario at hand. So, we have to take into account extracorporeal removal, which is zero right now with our patient, renal clearance, even if somebody is getting dialyzed, there could be residual renal function, and then hepatic clearance, if the drug is hepatically eliminated. Now, that's not going to be the focus of today's talk. Both of our drugs we're talking about, zosyn and vancomycin, have negligible hepatic removal, but that would be taken into consideration if that were a clinical concern. So, what we're going to focus on right now is the renal clearance portion. Now, we've talked about it. We know acute kidney injury is this abrupt reduction in glomerular filtration rate that has three classifications, pre-renal, post-renal, or intrinsic AKI. And what is unfortunate, and what we've talked about a lot today, too, is that assessing GFR in our patients, particularly those that are critically ill, is very difficult. Also, in those who develop AKI and have changing or non-stable renal function. We look to serum creatinine as our typical marker, our typical endogenous marker in which to evaluate and assess GFR, but we've already heard about several of those limitations. So, three of the big limitations that I think about, at least two we've talked about, is that GFR, a rise in GFR, can be attenuated, masked, or blunted because of things like large volume dilution, loss of skeletal muscle mass, and protein intake. Secondly, we know that serum creatinine rise after injury can lag by as much as 48 hours. These two things can inhibit us from even identifying AKI occurring when it has occurred in real time. And then lastly, there are non-GFR related alterations, particularly in skeletal muscle mass, that can impact your serum creatinine that are not accounted for by our traditional and our typical GFR estimating equations, and they're not accounted for by age and sex and race, so all of these things make serum creatinine not the best marker, but it is the one that we readily have across all of our institutions. Regardless of this, the question is how do we measure EGFR? We need to measure GFR in order to dose our patients. Now, this is not meant to be an exhaustive discussion of all of the different calculations because there's many of them, but a couple of the ones that I want to highlight. So, taking a step back, the gold standard of measuring GFR is actually to administer something like insulin, EDTA, or iohexol, then giving that as a continuous infusion, which undergoes primarily and only glomular filtration, giving it as a continuous infusion, measuring serial concentrations, urine or plasma, and then actually calculating glomular filtration removal. We obviously know that is not done in clinical practice, nor is it feasible for many reasons. So, what we're left with is those clinical markers, serum creatinine, as well as cystatin C, which we're going to talk about. Now, serum creatinine's role as a marker of GFR has been discussed since the 1920s. It wasn't until 1976 when Drs. Donald Cockroft and Henry Galt came together and developed the formula that we know today as the Cockroft and Galt equation that was pretty quickly picked up by the FDA and recommended by the FDA for pharmaceutical industries to utilize this equation in their clinical studies to guide drug dosing. Now, the issue is that historically, serum creatinine assays were not standardized, leading to issues in those drug dosing from those studies. So, then in 1999, the MDRD equation came out, which better predicted GFR than serum creatinine in the Cockroft and Galt equation. And then in 2009, the CKD-EPI was created, which sought to develop a better estimating equation for us and for our use, and they did with the CKD-EPI creatinine equation, which was then updated in 2001, and they removed race from it. This is now the recommended standard equation to estimate GFR at this time. I've listed those equations for you on the slide. What they also did in 2021 was add cystatin C. So, we now have three equations from 2021, the CKD-EPI creatinine, CKD-EPI cystatin C, and then the CKD-EPI creatinine cystatin C. So, I believe, and my assumption would be the reason the creatinine estimation equation is the one that's recommended is because cystatin C is just not readily available at all institutions or incorporated into clinical practice at this time. But what they found was that the best predictor of GFR was the CKD-EPI cystatin C, or sorry, CKD-EPI creatinine cystatin C equation, that last one on the slide for you. By no means do I recommend you memorize these equations, because you can see there's actually constants that are on there that are going to be determined by the actual value of serum creatinine or cystatin C and the patient's weight as well. Now, we've mentioned it, we've talked about it in a couple of our sessions too, but what is cystatin C? So, it is a non-glycosylated basic protein that's produced by all human nucleated cell, nucleated human cells that undergoes passive elimination by a glomular filtration. It's reabsorbed and then catabolized in the proximal carbon-polluted tubule. It is less dependent on age, sex, race, and muscle mass and dietary intake than serum creatinine, making it a much more attractive marker of estimating GFR. However, as I kind of alluded to, it's not been widely adapted into clinical practice, although there are a lot of studies that have started to attempt to find ways in which we can utilize it and optimize its role. Now, I don't feel like I'm the best person to be talking about this because I know we have one of our authors of many of our papers in the, as one of our speakers too, because this is heavily studied at Mayo, and they've looked at a lot of different antibiotics too, including vancomycin, which is one study that I want to highlight. So, incorporating cystatin C into vancomycin dosing better predicted vancomycin clearance. What they also found was that when cystatin C was incorporated into vancomycin dosing, patients who had their vancomycin doses decided because of the CKD epi creatinine cystatin C equation more often had therapeutic concentrations of vancomycin than when this drug was dosed based on Cockroft and Gold. So, although it's not readily implemented across many institutions, I think that this is probably going to be the way of the future. As we get more data and more studies that are incorporating cystatin C into equations and into drug dosing. So, I wanted to bring this points up to you today. Now, that leads us to kind of the take home point. So, what do we do when we have a patient who's developing AKI and we think we need to start adjusting their doses, how would we go about and approach this? Now, I actually, this might be a controversial opinion, but my recommendation would be to stop. We need to press pause. We need to take, what we do with my toddler is we take a break. So, we need to take a break on what we're about to do and stop just automatically dose adjusting all of our medications or discontinuing them. We've talked about that in our cardio and renal syndrome as well. We need to, what I'm suggesting is we take a step back and balance the risks and benefits of adjusting these medications or discontinuing them. What is the potential risks associated with maybe overdosing this patient a little bit? So potential medication related toxicities, but what are the risks of potentially underdosing this patient if we reduce the drug and discontinue it? So risk to efficacy would be a big one. Potential withdrawal would be another one. I can't say the number of times that I have gone into work in the morning on rounds and had seen a patient with a serum creatinine of 2 and every medication, digoxin was dose reduced or discontinued, anti-epileptics like Keppra was dose reduced and all of their antibiotics were messed with as well. When really we probably could have taken a step back and said this patient's baseline serum creatinine is 2. So it's actually not AKI or something along the lines of actually this jump was not enough to warrant a dose reduction at this time, but we'll continue to monitor. So my suggestion is to take a pause before we start to jump. Reach out to your drug information resources like your pharmacist if there are questions. Now when we're talking about designing dosing regimens, just for completion's sake, I want to make an important point and distinction. So some medications, particularly those with larger, longer half-lives, may require loading doses. Now the reason for this is it takes 3 to 5 half-lives to reach steady state. So to fill that tank, if you need to get to therapeutic concentrations quicker, you might have to give a loading dose. Now the reason that I bring this up is because loading doses do not require dose adjustment in the vast majority, almost all of the time, in patients with AKI, renal insufficiency, and SAGE renal disease, name them all, that what you're doing is you're filling the tank. The size of the tank has not changed because they developed AKI. Where you're going to change your dosing is how that tank is getting removed, how the drug is getting out of that tank. So your maintenance doses are likely going to be impacted because of alterations in kidney function, AKI dialysis. Now going back to our patient MJ, taking what we've learned. So patient's serum creatinine has risen from 0.9 to 1.5. We have a cystatin C, too. The cystatin C has reported back at 2.5. So the question is, now we've started this patient on zosyn, we've discontinued vancomycin, do we have to adjust the dose of zosyn? Now I don't, I'm not going to sit here and have you guys calculate this. I've calculated them all for you here. You can see the creatinine clearance from the Cockcroft and Galt equation reported out to be 30. The EGFR from the CKD epicreatinine is 51. And the CKD, the GFR from the CKD epicreatinine cystatin C is 32. I like this example because it shows the differences in some of these equations just based on patient's specific factors like age, weight, all of those things, cystatin C and creatinine. So in this case, what we had initially started this patient on was zosyn dose every four hours. I would bump them down appropriately based on the CKD epicreatinine cystatin C equation with a GFR of around 30 to 3.375 grams every eight hours. Now we're on day four of antibiotic therapy. This patient is now oliguric with 3 plus pitting edema, still requiring pressors. You could see his serum creatinine is up to 3.9 right now. He's borderline hyperkalemic. Nephrology is consulted. It's decided to initiate renal replacement therapy and continuous renal replacement therapy is decided to be initiated as the modality. Now, does his dosing need to be adjusted? So we'll talk about the remaining factors that are going to influence our drug dosing that are going to specifically apply to renal replacement therapy. So we're going back to total body clearance, looking at that extracorporeal clearance specifically. And we're talking about continuous renal replacement therapy. We need to know and understand the modality that is selected. The modality is going to determine how much and the degree to which drug is removed. So in our convective modalities, the sieving coefficient is going to determine how much drug is able to be removed and passed through that filter membrane. It reflects the concentration and the ratio between drug and the plasma to the ultrafiltrate. Now how much drug is removed is going to depend on whether the replacement fluid is before or after the filter membrane. So you could see in post-dilution modalities, it's pretty simple. The amount of drug removed is going to be dependent on the ultrafiltration rate. It's a little more complex with our pre-dilution modalities because your plasma is going to be diluted by that replacement fluid. And that's going to be determined by the blood flow rate. I'm obviously simplifying a lot of very big factors here. But you can see the formulas that we would utilize to calculate how much drug is removed in that pre-dilution modality. It's going to take into account both the blood flow rate, the ultrafiltration rate, as well as that sieving coefficient. Now in our diffusive modalities, like CVVHD, we're going to look to the saturation coefficient, similar to the sieving coefficient. But that saturation coefficient is going to determine how much drug is able to be removed. And that in combination with the dialysate rate. I feel like I'm the only person besides nephrologists who cares about the dialysate rate. But that's going to be key in determining how much drug is removed through CVVHD. And then in our dual modalities of CVVHDF of the convection and diffusion, both the ultrafiltration rate and the dialysate rate are going to be taken together and multiplying by the saturation coefficient to determine how much drug gets removed. Now some drug-specific properties that are going to impact all of what we just mentioned is the molecular size and weight of the drug in question. So the molecular size of the drug is going to determine how much drug can be removed. Because the larger the molecule, the less likely it's actually going to get removed through dialysis. The good thing to note about this, though, is that most of our medications that we're utilizing, antimicrobial agents and some that we use in the ICU, are relatively small in size. So this isn't too much of a factor. I've listed a handful of those for you on the slide with their molecular weight. But the pore size of the filter itself is going to say how big the molecule can be that can go through. I am by no means an expert in filter membranes and their various sizes and cutoffs with their pore size. But to just kind of introduce a few concepts, there's low-flux membranes that allow minimal to no removal of those smaller molecular weight, or sorry, larger molecular weight drugs. And then there's high-flux membranes that may have and allow significant removal of drugs with higher molecular weights. And then there's even fancier ones, like high-cutoff membranes, high-retention cutoff onset membranes that have cutoffs that are closer to native kidneys. Some have a limitation of an albumin leak occurring. Others do not have that limitation. And that leads us to protein binding. We know that protein binding is the property in which a drug may bind to our plasma proteins, primarily albumin. Why this is important is because only free drug can be removed through renal replacement therapy. Because like I just mentioned, the majority of our filter membranes, almost all, are going to prevent anything that is the size of or larger than albumin from going through that filter. This is like I had mentioned, the main determinant of the sieving coefficient as well as the saturation coefficient. Now like every concept I'm talking about and that we're talking about today, this is nuanced and can be complex because protein binding itself can be altered based on some patient-specific factors, like in the presence of uremic toxins, at various blood pHs, in settings of patients who might have hyperbilirubinemia. And if there is competition of other drugs for plasma protein binding. Now going back to the drugs that we're talking about today, zosyn and vancomycin, remembering our pharmacodynamic properties, I want to talk about some data associated with these drugs and how it can help guide our drug dosing. So beta-lactams, I think I've, you know, pounded it into this talk many times. It is our time-dependent antibiotic. Now what that actually means, we haven't had a chance to talk about. So what that means is, and what has not yet been agreed upon in the literature, is how much of that dosing interval needs to be above the MIC. Is it 40%, 50% of the dosing interval should the plasma concentration should be above the MIC? Others would say, myself included, that it probably should be closer to 100% of the time the patient receives this drug, that concentration should be above the MIC. Others might actually say it should be above four times the MIC. Regardless, as I had mentioned, what we know is that the best way to optimize this is to give the drug more frequently. Now this is where the concept, this hot topic in the antimicrobial world is of giving a continuous infusion or an extended interval. Now that would conceivably do this. There's not a ton of, or I guess I should say the jury is still out on whether or not this is truly the best method, especially in critically ill patients and those requiring renal replacement therapy. I would say there is a gap in patients who require renal replacement therapy. There are some logistic limitations, like you would need a dedicated line. You might need a central line to maintain line patency. And there's always the potential issue of compatibility issues and not having enough access in order to do this. The pie-in-the-sky best case approach would be with therapeutic drug monitoring. But I think we're probably all pretty aware that this isn't something that is readily available and the literature shows variable concentrations when it looks at therapeutic drug monitoring anyway. When we look to the specific studies regarding Zosyn in patients receiving renal replacement therapy, continuous renal replacement therapy, there's actually a lot out there that can help guide our drug dosing. One of the studies that I like to highlight, this is a study of 16 patients receiving CVVH. They did a pharmaco, a Monte Carlo simulation study of that population. And they had varying degrees of residual renal function. So the graph on the left-hand side of this slide will show you patients that had virtually no residual renal function remaining. They had good probability of target attainment. And their target was 90% of the time above the MIC. They had good target attainment up to an MIC of 16 with their dosing intervals of every six or every eight hours. Once the MIC exceeded 16, they did have more difficulty in achieving that PK PD parameter, which is probably okay because I wouldn't be using Zosyn in somebody with an MIC greater than 16 anyway. Now if you look to the right-hand graph, you can see these patients had some degree of residual renal function remaining. And they had difficulty or I should say good probability of target attainment up to an MIC of 1. But then difficulty once that MIC exceeded 1. And they needed to have doses more frequently up to every four hours. And even then, once you pass an MIC of 2, it became difficult to obtain that pharmacodynamic parameter. I like this example because it shows that it's not just this patient is on CRRT, this is my dose. You have to take into account other patient-specific factors. And even this study didn't incorporate things like dialysate or ultrafiltration rate because it was CVVH. So there are still other things that would have to be added on top of these concepts. So I've listed some example regimens for Zosyn in continuous renal replacement therapy for you on the slide. It is a range because, again, you have to take into account all these factors, 3.375 up to 4.5 grams anywhere from every six to eight hours, maybe even more frequently depending on the patient's scenarios. So when I would go to our more aggressive dosing is in somebody who had high dialysate, ultrafiltration rate, whatever modality they're on, high rates of dialysis, if they also were at extremes of weight, we didn't really get to talk about that very much, and in patients that had residual renal function as well and those that have higher MICs for their pathogen that's isolated. For completion's sake, I've also listed continuous infusion and extended interval dosing for you as well. Now pivoting to vancomycin, I know MJ, our patient, is not on vancomycin at this time, but just to bring it all home, as I feel like we, you know, we use vancomycin quite a bit. I call it vitamin C for a reason. So vancomycin is our AUC-dependent antibiotic with a goal AUC to MIC ratio of anywhere from 400 to 600 is typical. This is probably going to get difficult once the MIC of the pathogen exceeds two, just as a note. So alternative agents are often looked to in those settings. Now prior guidelines recommended targeting trough concentrations anywhere from 15 to 20 milligrams per liter, but the updated vancomycin dosing guidelines actually recommend to calculate the AUC and target this goal of 400 to 600. Now this can be calculated or you can get an AUC if you have Bayesian-derived programming that has a pharmacokinetic model embedded in it. It would typically require two plasma concentrations of vancomycin, ideally a peak and a trough concentration. That's not readily available at all institutions. My institution has not adopted this practice yet. So in that case, we still would utilize our trough concentrations to guide our dosing. We've already talked about the concept of loading doses may need to be utilized to achieve this target parameter, and this stands true in somebody who would require CRRT. Now I'll typically load 15 to 20 milligrams per kilo in somebody on CRRT if I think they're massively vasodilated, then I would go up to 25 milligrams per kilo. Now a typical CRRT dosing regimen, again, there's no right or wrong, but typically what you would see is anywhere from 10 to 15 milligrams per kilo every 24 hours. I actually err on the lower end, the 10 milligrams per kilo of this dosing regimen. There is data to show that higher levels, this 15 milligram per kilo, may result in super therapeutic concentrations, but I would go to that dosing, the end of the dosing range in somebody who had high dialysate ultrafiltration rates, who had a residual renal function as well. Now going back and bringing this all home to our patient, MJ, so CRRT is initiated, they initiate CVVHDF at a dialysate rate of 3,500, ultrafiltration rate of 150, and he has residual renal function, urine output at 50 an hour. So the question of does the zosyn that's dosed right now at 3.375 grams every eight hours need adjustment? Now typically this would be a good dosing regimen in someone on CRRT, however, what we're working with is dual modality of clearance with ultrafiltration and dialysate and diffusion, so you're getting both of those removals, so you have a higher rate of clearance, residual renal function as well. So because of this, I actually think it would be very reasonable to increase your frequency in this patient anywhere from every four to every six hours, probably every four. He is also a larger patient, if you recall. Now the last concept that we're going to talk about is this is all fine and dandy, but what happens when we then change our modality of renal replacement therapy? I won't say it's the bane of my existence, but it's kind of the bane of my existence that every day we do something different. That's great. It's okay though. So when we have IHD, CRRT, PERT even as well, how do we change our drug dosing? Now what I do, the way I approach it, there's no science to this, it's more of an art, is I just think of in this patient, what would I do with each modality and then change my dosing based on the modality that they're receiving. Now in drugs that have more narrow therapeutic windows, vancomycin, aminoglycosides are going to be great examples. I'm going to take a lot more care into the timing of those doses. Beta-lactams, where I'm not as worried about overdosing, I'm not as worried about when the last dose was given, I'll just freely change between my intervals. So if I have somebody, vancomycin for example, if I have someone on CRRT that gets discontinued, they're getting transitioned to IHD, and I just gave them a dose of vancomycin, I might actually allow two IHD sessions to occur before I then go to a supplemental dose after dialysis. On the converse, if I have somebody who I just loaded with vancomycin and CRRT gets initiated right then, I might actually allow a full dosing interval up to 24 hours to pass on CRRT before I administer the next dose. Now we didn't really talk about PERT, this Prolonged Intermittent Renal Replacement Therapy, but the way I approach dosing in this will all be based on the prescription or the length that they're on PERT therapy. So my institution often does four hours of IHD or four hours of dialysis followed by two extra hours of ultrafiltration. I'll treat that like normal IHD for my dosing. But if I have somebody who's going to get six, eight plus hours of PERT, that's when I'm going to consider giving either a supplemental dose or going to CRRT dosing while they're on PERT and then resuming IHD dosing once that's discontinued. I lost the mouse again. Nope. Yep. Okay. All right. So going back to MJ, CBVHDF is discontinued in each transition to IHD. He is now anuric, so that residual renal function has gone out the door. We had him originally on Zosyn 3.375 grams every four hours. Do we have to change this? And yes. So this is when I would go to IHD dosing. The IHD dosing that's standard at my institution is to give it every 12 hours. So that's what I would recommend in this instance. Now to bring it all home, I've talked about a lot of different concepts. So we have to keep in mind total body clearance, all of these patient-specific factors when we're guiding our drug dosing. And the biggest thing I can say is understanding that this is not a one-size-fits-all approach. We have to take into account all of these pieces in order to customize our dosing and our medication utilization in our patients that are critically ill, develop AKI, or require dialysis.

medication dosing

critically ill patients

acute kidney injury

renal replacement therapy

antibiotics

glomerular filtration rate

continuous renal replacement therapy