I'm going to start introducing the session. My name is Javier Neira. I'm from the University of Alabama at Birmingham, and I have the pleasure to chair this session here with Dr. Jenna Yesajan and Dr. Sacha, Gretchen Sacha, and we have representation here from nephrology, critical care medicine, and also pharmacy, and the idea is that this session is a little bit interactive. So we're going to try to cover very briefly these three topics with around 15 minutes each, and we're going to leave 10 minutes at the end for questions, interactions, discussion. I think, and we are happy to entertain with any of you guys after the session to address more specific questions or things. So the first portion, I want to remind you that all sessions can be evaluated through the mobile app and also through the online program. So at the end of this session, please try to evaluate. So they keep bringing some CRRT talks on the meeting. The first talk is going to be patient selection, timing, modality, and dosing, and we're going to start. These are my disclosures. In the outline, I'm going to talk about indications of RRT initiation, the concept of early versus standard initiation of RRT, a little bit of CRRT modalities, how to differentiate between moralities and the principles of diffusion and convection, and then we're going to talk about prescription and dosing of the total effluent dose of CRRT. When we talk about indications for renal replacement therapy initiation in a patient with AKI, particularly those that are critically ill, we have classic indications on the left that we recognize that prompt any intervention very quickly, like hyperkalemia, severe metabolic acidosis, volume overload, oligoannuria, uremic complications, and drug intoxications. Sometimes patients with hemodynamic instability, hypercatabolic states, sepsis, patients with increased intracranial pressure that are in AKI and have little residual of kidney function can benefit from RRT as well. The important differentiation between CRRT and hemodialysis, of course, CRRT is continuous, but the blood flow rates are very different. In CRRT, typically the blood flow rates are between 100 and 200 mLs per minute. With hemodialysis, we prescribe higher blood flow rates, 350-400 mLs per minute. The dialysis fluid rate is very different. In CRRT, typically it's about 2-3 liters per hour, that it's approximately 33-50 mLs per minute. In the hemodialysis session, we prescribe 500-800 mLs per minute of dialysis fluid rate, and for that reason, the hemodialysis device use the water system in the hospital, and this is purified water. In CRRT, we use pre-made baths, 5-liter baths. Then the concentration of the electrolytes can vary depending on what solution is available, and similar for hemodialysis, they can do the concentration dilution next to the HD device. Anticoagulation, for CRRT, we prefer a mode of anticoagulation to keep the circuit viable with less clotting. Typically regional citrate or systemic heparin are the most common forms of anticoagulation. When we talk about advantages, we need to recognize that CRRT can provide better hemodynamic stability because we have a lower ultrafiltration rate. This means that we can expand the treatment and the fluid removal of the patient to customize the specific needs. Hypothermia sometimes helps because the peripheral vasoconstriction will help the refilling in this patient. There is a slower reduction in the extracellular fluid osmolality, and for this reason, there is a slower change also in the ECF electrolyte concentrations, and this is prone to less arrhythmias when we compare to the hemodialysis device. It's better fluid regulation, you can customize the prescription a little bit longer for extended periods of time, and also it has a better solute control because you can keep the patient continuously on treatment and do infiltration. Lower bleeding risk comparing to hemodialysis that sometimes require anticoagulation systemically, and is more physiologic, trying to recreate what the kidney does in a 24-7 fashion. There are also disadvantages. Most of the time require anticoagulation to keep the circuit viable. Hypothermia could be a problem in certain patient populations, for example, post-cardiotomy shock, where these patients are really very prone, you need to really warm them back, and hypothermia may not be desirable in these patients. Hypophosphatemia and other electrolyte abnormalities are very common, and now we recognize the importance of keeping these electrolytes at adequate levels, especially to preserve skeletal muscle function in these patients. There is a slow correction of severe electrolyte abnormalities comparing to hemodialysis. A patient with severe hyperkalemia will correct slower with CRRT versus HD. So if a patient is really having electrolyte, severe electrolyte abnormalities with EKG and can't tolerate hemodialysis, that should be their preferred modality to start. Limits patient freedom for procedures, for studies, for physical rehabilitation. Although this is changing, because these days we are trying to promote rehabilitation in patients on extracorporeal support devices, and that includes CRRT, it's more intensive for the nursing staff, and it conveys higher costs related to all these issues. Now when the question between comparing CRRT versus hemodialysis in patients that can't tolerate both has arised, there have been in the last 20 years some clinical trials, small multi-center, some of them, that suggested that if a patient can't tolerate both modalities, there is no benefit in mortality if you start a patient on CRRT versus hemodialysis. Of course, patients that cannot tolerate CRRT are not represented in these clinical trials. These patients were excluded from the randomization. A better question is perhaps when to initiate the treatment, and if there is a benefit in some patients to do it proactively early versus a standard initiation of RRT. Most of the time, the reasons we initiate a patient a bit more proactively is to manage fluid overload and to have a faster restoration of acid-base balance. Patients, for example, very difficult to ventilate, that they need some pH, some transfer of bicarb to try to stabilize hemodynamics. And these patients sometimes can benefit from a little bit of delivery of bicarb through the RRT device. Accelerated removal of small and middle-sized molecules. Middle-sized molecules, particularly those that are inflammatory mediators in patients that are very hypercatabolic, in septic shock. There could be some benefit in this mitigation of inflammation of all these devices for blood purification, although studies are still undergoing. Fluid overload is very important and recognized that has a direct relationship with mortality. And this relationship is dose-dependent. And this, of course, is related to initiation of RRT. Because if we keep waiting and the patient is not making urine, we're not able to maintain adequate fluid balance, then the odds of mortality continue to rise. This is a specific cohort of patients with sepsis. And you can see that those response relationship between the cumulative fluid balance on the x-axis and the standardized mortality ratio in the y-axis. Similarly, fluid overload can be associated with kidney recovery. This is a study from University of Michigan, where they evaluated different parameters at the time of RRT initiation. And the outcome was independence of dialysis one year after discharge. Among many parameters, fluid overload was one of them, independently associated with kidney recovery. And this brings the question, if we limit fluid overload, can we promote kidney recovery in some patients? This is a different study, where fluid overload at the time of CRRT initiation was evaluated in critically ill patients. And you can see, again, this dose-response relationship with an epidemiological outcome that is major adverse kidney events at 90 days. That include a composite of mortality, dialysis dependence, and also a deterioration in GFR, 50% from baseline. At the same time, we need to be cautious to initiate proactively a patient on RRT, because many patients, even with severe acute kidney injury, can recover kidney function. There are renal replacement therapy-related risks, a lot of them related to the catheter insertion. And also, there is a cost with every extra day of RRT we provide to our patients. In the last, I would say, seven years, there has been many clinical trials trying to address early proactive initiation of RRT versus more standard initiation based on specific indications of severe electrolyte, acid-base abnormalities, and fluid overload. And you can see, since 2016, the ELAIN trial, AKIKI trial were published, and then subsequently IDL-ICU-START-AKI. I'm going to briefly comment on these studies, and this slide summarizes a lot of the important facts of these trials. The ELAIN trial was a study mostly in cardiac surgery patients, single center, and is the only study that showed that early initiation of RRT, when the patient meets criteria of stage two or three AKI, plus a positive biomarker of kidney injury, was associated with lower mortality at 90 days, comparing to a standard group that was initiated by classical indications of fluid overload, electrolyte, acid-base abnormalities. Subsequently, the AKIKI trial that was mostly medical ICU patients, a lot of sepsis representation, IDL-ICU that was a study specifically in septic shock patients, START-AKI that was a study in multiple ICUs, multinational, and this is the largest study so far, close to 3,000 patients, addressing the same question of initiation of a patient with severe AKI in an accelerated way versus standard indications, and these studies have shown no difference in mortality, either at 60 or 90 days. Now the difference in timing that you can see in these studies was between 24 and 48 hours at the most between the two arms of accelerated initiation after severe AKI criteria versus the standard indications, and you can see none of the studies except Elaine show that there is any benefit of accelerated initiation. Now the START-AKI show also that patients that survive had more kidney dependence on kidney replacement therapies, any type of dialysis at 90 days, if they were initiated in the accelerated arm, something that has bring back this concept of try to limit exposure to extracorporeal circuits in particular dialysis devices in patients that really don't meet any specific criteria of solute of fluid management, so we need to keep in mind those findings. So with this in mind, we should summarize saying that to initiate a patient on RRT, we should basically take into consideration the severity of acute kidney injury, the trends of creatinine urea trajectories, urinary output fluid status of the patient, electrolyte arrangements, acid-base status, and the complications of uremia. At the same time, we should take into consideration the severity of the critical illness, what are the events leading to AKI, the status of non-kidney organ dysfunction, the degree of fluid overload, the comorbidity of the patient, and the trajectory of the critical illness. We should take into consideration potential risk of RRT, how difficult is to insert the line on that patient, hypotension during RRT, and the detrimental effects of it. And also that we're providing non-selective clearance, and therefore we can remove nutrients and drugs that are important for the patients, particularly in the early stages of shock. Other factors, where are we practicing? What machines we have available, the availability of our staff, the patient relative wishes, and the futility prognosis of the patient for receiving the treatment. So what we need, and this is a work in progress, is to evaluate the prediction of the trajectory of the patient, right? So we have four patients here with different trajectories. We would like to perhaps initiate RRT more proactively in the patients on the top, where the progression of the AKI and complications related to AKI can be accelerated, and versus waiting in patients on the bottom that can recover kidney function if we just keep supporting them during the early phases of shock. Kidneys have limited capacity, and therefore the degree of an impact of fluid and metabolic derangements vary between patients. So for any intervention that we do, we should remember that the U-shaped relationship between harm and benefit, and the intervention on the X-axis. That means that in the case of initiation of RRT, early for one patient, maybe too late for a different patient. So individualization of the initiation decision is what is recommended. In the last couple of minutes, I'm going to cover a couple of principles of CRRT that I want you to remember. Of course, the acronym, CONTINUOUS, VINOVINOUS, HEMODIALYSIS, HEMOFILTRATION, and HEMODIAFILTRATION relate to these principles of dialysis that I want you to remember. The first one is the clearance by diffusion, and clearance by diffusion means the movement of solutes across the hemodialyzer from high concentration to low concentration, and movement continues until equilibrium is reached. This is good for small solutes. And if you want an analogy, you can do the analogy of the teacup, where the concentration is very high inside the back of your tea, and it's going to diffuse across the back through the water, right? So this is diffusion. Now, if you see the filter to provide and maximize the concentration gradient across the hemodialyzer, you have the blood coming in one direction on the top, and the dialysis fluid coming in the other direction on the bottom, and solutes will move from high concentration to low concentration. Assuming we have a patient with hyperkalemia, perhaps we are removing potassium from the blood to the dialysis fluid through diffusion until this concentration gradient reach equilibrium. You set up the device. You can set up the device only to provide diffusion in CBBHD mode, hemodialysis. The other principle is clearance by convection. In convection, we move solutes associated with fluid movement, and this is a solute drug. Movement is dependent on the rate of fluid movement, and this is called the total ultrafiltration rate. There is no gradient needed, and this is good for middle-sized molecules. So here in the diagram, you apply a pressure to the blood compartment. You're going to move fluid across the hemofilter, and you're going to drag solutes with it. With that, the analogy is the preparation of your coffee cup. You put the filter on the top, and then you put your coffee there, and then pour water that through gravity is going to apply a force that is going to move solutes from the top of the filter down to the water. So here in the diagram, you only have blood coming in one direction. You apply a force, and this is going to move fluids, and with that is going to drag solutes, and this is the principle of convection. When we talk about convection, we talk about continuous veno-venous hemofiltration. Sometimes H or HF, both acronyms are used, and here you can see that because you are moving fluid across the hemofilter, you need to give that fluid back to the patient as pre- or post-replacement fluid in the configuration of the machine. You can do a hybrid treatment where you provide both principles. You add the dialysate fluid there, counter current with the blood flow, and the replacement fluid according to the convection treatment that you're giving. So when you think about a prescription, you talk about the modality, and we always recommend to standardize your modality. The effluent dose that is in the CRRT is equivalent to your clearance. You need to determine how much fluid removal the patient should have, the blood flow that we always recommend to set it up, very standardized, and then the type of anticoagulation. When you prescribe those, you need to consider that not everything you prescribe the patient receive. There is always a gap between the prescription and the deliverables. When we talk about those, this is the data. The total effluent that a patient should receive on average should be between 25 and 30 mLs kJ per hour, and this comes from two landmark studies that are highlighted there in red that are the ATN trial and the renal trial. These studies compare a standard dose of 25 or 20 mLs kJ per hour of the liver dose versus a higher dose of 35 to 45, and show no difference if you provide the patient's higher total effluent dose. Now remember, a dose of 30 mLs kJ per hour in an average 70-kilogram patient is about 30 mLs per minute. So that means comparing to the normal clearance of the kidney is much lower, it's a fraction of it. Normal clearance of the kidney is 120 mLs per minute. So the patient only needs on average a dose between 25, 30 mLs kJ per hour, and this is proven in clinical trials. Why? In part because CRRT is only providing filtration and not the other functions of the kidney of reabsorption and secretion, and therefore there are things that are important for the patients that we are non-selectively clearing to, and this could be part of the explanation why a prescribed dose should be around 25, 30 only on average. Transiently, patients may require higher versus lower doses. So with that, I'm going to stop there and saying that CRRT is the preferred type of RRT for critically ill patients that are hemodynamically unstable. Early RRT for one patient may be too late for a different patient, and RRT initiation should be therefore individualized. A specific CRRT modality does not affect patient outcomes. You should do the modality that is more available according to the devices you have and the expertise you have in your program. And also the recommended CRRT total effluent dose should be 25, 30 mLs kJ per hour, although it may transiently vary according to specific patient needs. Optimal provision of CRRT requires a multidisciplinary teamwork, and you can see here in the panel, and we will continue this session in the next few minutes. Thank you very much. I'm going to introduce Dr. Gretchen Satcher. She's from Cleveland Clinic, and she's one of our pharmacists with expertise in CRRT. She's going to talk about medication dosing considerations in RRT. Thank you for the introduction. So like he said, we're going to talk about medication dosing. It's a concept that I'm sure everybody feels so comfortable with. So who here in this room feels like they are 100% comfortable dosing medications in patients requiring renal replacement therapy? Not one person except for me, and even I'm questionable in raising my hand at times depending on the medication. So we're going to talk about a bunch of concepts today that I'm hoping can get you guys to feel a little bit more comfortable. Maybe we can get a half hand raised by the end of the talk with some of you guys. We're going to talk about a lot of different concepts that I, as a pharmacist, take into account when I am dosing and optimizing my medication regimens in my patients that have AKI, and then those that progress to requiring renal replacement therapy. When we talk about specific medications, I'm going to focus today's talk on our antimicrobial agents, because again, we think that these are some of our most common and important medications that we're dosing in this patient population. Now I don't think I need to belabor these concepts to those in this audience right now. We all know that when prescribing and administering medication, dosing matters. And we have to balance and outweigh the potential medication-associated toxicities that can be seen when we overdose patients, and the potential therapeutic failures that may be associated with underdosing. Patients who develop AKI and require renal replacement therapy are at both of these phenomenons occurring, because there's a relative lack of data guiding our drug dosing in this population. It also shouldn't come to a surprise to all of us when we talk about critically ill patients, which will be also another focus of our talk today. These patients, when they develop AKI and renal replacement therapy, the vast majority of them are going to require a medication dose adjustment in at least one or more of their medications. So the question that gets posed to pharmacists on a daily basis is, how do we do this? How do we go about optimizing our medication dosing in this population? And unfortunately, the answer is very convoluted and complex. But I'm going to go through a lot of concepts today that are going to help give some insight into the thought processes that we have when we're developing medication regimens for these patients. The first concept is the concept of total body clearance. So when we're talking about patients that require renal replacement therapy, it is not just about clearance through that extracorporeal circuit or through renal replacement therapy. You have to think of the concept of total body clearance or the sum of all of the clearance processes that are going on at one time. So that would be extracorporeal clearance or renal replacement clearance, in addition to any residual renal function clearance that might be remaining, and then adding on hepatic clearance if the medication is hepatically eliminated as well. Now when we talk and focus on that extracorporeal or RRT clearance, the modality is going to determine how much drug is removed and how we calculate the drug removal. So we've already talked about all of the different modalities. So when we look at our convective therapies, the seething coefficient is going to determine how much drug is able to be removed through that convective modality. And that's going to be determined by plasma protein binding, which we'll talk about. Now in convective therapies, because there's this is the replacement fluid before the membrane or after the membrane, it can get a little complex. So in post-dilution modalities, the ultrafiltration rate in combination or in multiplication with the seething coefficient is going to determine drug removal. But in pre-dilution modalities, you have to take into account the plasma blood flow rate because your plasma is diluted by the replacement fluid. So you can see the calculations for those on the slide. Now in our diffusive modalities, the saturation coefficient is going to determine how much drug gets able to pass through that filter membrane. And when we talk about diffusive modalities, that in multiplied by the dialysate rate, it's going to determine your overall drug clearance for diffusive modalities. And then for our hybrid modalities like CBV HDF, both the ultrafiltration rate and the dialysate rate are going to need to be taken into account and multiplied by the saturation coefficient. I wish it was that easy. As we keep going through, we're going to add a level of complexity. So when we talk about how to then apply that to our patients, you have to take into account many patient-specific factors and drug-related properties as well that is going to impact how much drug is actually able to be removed. So we'll talk about some drug properties, the pharmacokinetic and pharmacodynamic considerations. We're going to go back to pharmacology class. And then we'll talk about patient-specific scenarios. And then what do we do if their renal replacement therapy modality is changed or interrupted? So the first drug-related property to talk about is the molecular size. So the larger the molecular size or weight of the drug in question, the less likely it's going to be removed through dialysis and our renal replacement therapy modalities. Now, the good thing is the majority of our most commonly used medications in the ICU, especially our antimicrobial agents, are relatively small in size. And I've listed a handful of them for you on the side of our more common agents I'll see used in the ICU. What will also impact drug removal in relation to the molecular size is the pore size of the membrane. Now, I am by no means an expert in membranes, and you're going to hear more about them in the next session. But there are low-flux membranes that are going to have minimal to no removal of our larger drugs. And then there are high-flux membranes that are going to have some significant removal of your larger molecular weight-sized drugs. And then there's these fancier membranes, like our high cutoff membranes and our high retention onset, that also have their own strengths and limitations as well, but will allow removal of some larger drugs. The next concept is plasma protein binding. And we know that when we talk about protein binding, we're referring to drugs that are primarily bound to the protein albumin in our blood. So only free drug can be removed, because the majority of our filter membranes are not going to allow removal of molecular weights that are the size of or larger than albumin. So if the medication is free and not bound, that is at risk of getting removed. However, and as I talked about this, how much is removed is determined by the seeding coefficient and the saturation coefficient. But your protein binding can also be impacted by patient-specific factors, like if there's the presence of uremic toxins based on the blood pH, as well as in scenarios of hyperbilirubinemia, and if there are other protein-bound drugs that are competing for albumin. The last drug property to talk about is the volume of distribution. So this represents the amount of drug in the body divided by the plasma concentration. It's represented as a volume. The larger the volume of distribution, the more extensively the drug is distributed into the tissues and less remains in the intravascular space. This is important because we're only removing drug through RRT that is in the intravascular space. So if you have a patient who's receiving IHD and they're receiving a drug with a large volume of distribution, what you will get is removal of the drug in the intravascular space. Once that session is complete, you will get redistribution of the drug from the tissues and overall negligible drug removal. In CRRT modalities, it's a little bit different. What you'll see is removal, redistribution, removal, redistribution, more of an equilibrium. So you'll still get overall negligible drug removal, but over time, it might be more than your IHD modality. Another piece to know with volume of distribution is when we talk about our critically ill patients, they can have a very significantly increased volume of distribution compared to non-critically ill patients. We can see with our antimicrobial agents like beta-lactams, vancomycin, as well as amino glycosides, you can see an almost 100% fold or 100% increase in their volume of distribution of these medications. Now we're going to take our drug-related properties and then apply them to the pharmacokinetic and pharmacodynamic effects in our patients. So pharmacokinetics are talking about how a drug moves through a body, absorption, distribution, metabolism, elimination, and then our pharmacodynamics is talking about and referring to the actual clinical effects of our drugs and how they're impacting our patients. Now in patients who are critically ill, they have alterations in their PKPV properties. So we talked about volume of distribution is increased. Tissue penetration can be reduced. Clearance can be increased if they have augmented renal clearance or reduced if they are a population we're talking about, those with AKI requiring renal replacement therapy. Now the thing that we don't really know is how these pharmacokinetic alterations are going to impact our pharmacodynamics and our overall clinical outcomes, but what we're left with is trying to optimize our pharmacodynamic parameters. So when we talk about our antimicrobial agents, there are different pharmacodynamic targets that we're trying to achieve, and it depends on the antibiotic class on what target you're trying to achieve. So there's three main pharmacodynamic targets. There are drugs that are concentration-dependent, there are those that are time-dependent, and there are those that are AUC-dependent. So our concentration-dependent drugs are our aminoglycosides, fluoroquinolones, metronidazole, daptomycin. What matters here is that peak concentration to the MIC, the minimum inhibitory concentration of our pathogen, that ratio. So what you will see to optimize this parameter is high aggressive doses. This is why you should see high doses of aminoglycosides in your decompensating septic shock population regardless of renal function. Now our time-dependent drugs, you don't have to get a peak concentration, you just have to have your plasma concentration above the MIC for a specified period of your dosing interval. So the way to optimize this parameter would be to give more drug more frequently. This is your beta-lactams and linazolid is another example. And then lastly, our AUC-dependent drugs, so vancomycin and macrolides. What matters is the area under the concentration time curve. It's that shaded area in this graph. So the way to optimize this parameter is to give more drug more frequently. Now to start to tease out some of our specific classes, when we refer to beta-lactams, these time-dependent medications, we talked about we need to achieve a specified period of the dosing interval above the MIC. So there's a lot of variation in what the recommendation is. Should it be 40% of that time is above the MIC? Should it be 100% of the time we have other concentrations above the MIC? Others will even say it's not just above the MIC, it's four times the MIC. So regardless of what the actual parameter that you're trying to achieve is, or what that goal is, the best approach is to increase the frequency of your dosing interval. Now this will also bring into light conversations about should we just give a continuous infusion or should we do an extended infusion? Now in our patients that are requiring continuous renal replacement therapy, there's not a ton of data in this realm. It is there, but it is not super strong, I would say. And there are some limitations associated specifically with the approach of giving a continuous infusion. You will need a dedicated line. You might need a central line to maintain line patency. There can be compatibility issues with other medications. So this is when this concept of an extended infusion might be an attractive option for some patients as well to really optimize the time above the MIC. The pie in the sky best approach would be therapeutic drug concentration monitoring, but we all know that that's not readily available. So what we're left with is just extrapolating what we know to our practice, which is give more drug more frequently. And I'll talk about some examples of how to optimize your dosing. So if I specifically pick out at least the workhorse at my institution, which is piperacil and tezobactam or zosyn as I will refer it to, this is a pharmacokinetic study of a PK modeling study, a Monte Carlo simulation of 16 patients who are receiving CVVH. And they looked at patients and determined their ability to achieve that PK PD parameter, basically the percent of probability target attainment. The graph on the left-hand side is showing patients that had no residual renal function. What you can see with the two dosing regimens that they looked at was great target attainment all the way up to an MIC of 16 of the pathogen. Once the MIC exceeded 16, they had difficulties achieving that PK PD parameter. They needed higher doses as in more frequent dosing interval to be able to achieve that. This is probably okay, because I would not utilize this agent with a pathogen that had an MIC that's greater than 16. But when we shift our focus to the graph on the right-hand side, this is a population of patients that had residual renal function. And what they found was good target attainment only up to an MIC of one with their dosing regimens. Once the MIC exceeded one, they had to utilize those higher dosing regimens of every four hours to achieve this PK PD parameter. Now, I like this example because it shows that it's not just about extracorporeal removal, but you also have to take into account those patient-specific factors. And this is only looking at and incorporating residual renal function. So when we talk about a specific regimen for patients for Zosyn on CRRT, your dosing can vary anywhere from 3.375 to 4.5 grams every six to eight hours. Now, I would push my dosing, push my frequency in patients that had residual renal function, had a pathogen with a higher MIC. Those that were receiving higher than the standard regimen or standard dialysate rate, so which we talked about was 25 to 30 mics per kilo per minute. So if they are above 30 mics per kilo per minute on their rates, I will push my dosing. I will also do so in patients that have obesity or at extremes of body weight. And then I've also listed continuous infusion and extended infusion regimens for you as well for your reference. Now, the second and last specific agent that we're going to talk about is vancomycin. So we said this is an AUC to MIC dependent drug. The goal AUC to MIC ratio is anywhere from 400 to 600. Typically the way that this is monitored, this agent is just with trough concentrations with the goal of anywhere from 10 to 20 milligrams per liter. However, the new guidelines recommend actually calculating the AUC and then optimizing in that method. And you can get AUC monitoring through Bayesian derived programming that has a PK model embedded in it after receipt or drawing two vancomycin levels, preferably a peak and a trough concentration. This isn't available everywhere. So if you have trough monitoring, that is fine as well. Now, when we talk about our critically ill population though to optimize this parameter, you likely will need loading doses. So you might see higher doses that are prescribed for that initial dose, anywhere from 15 to 20 milligrams per kilo with a maintenance regimen that is then adjusted for their renal function or renal replacement therapy needs. Now, what a regimen might look like for someone receiving CRRT is anywhere from 10 to 15 milligrams per kilo every 24 hours. Now, I actually lean on the lower end of this, 10 milligrams per kilo for my standard patient because there is data that has been shown supra therapeutic concentrations with doses as high as 15 milligrams per kilo. But when I would push my dose, would be patients that have residual renal function and those that have those higher dialysate rates, I would automatically start out on my higher end of my dosing range. And the take-home point with vancomycin is monitor your concentrations. It's a narrow therapeutic window. We don't want to overdose. We don't want to underdose. So I would utilize and leverage my trough concentration monitoring for this agent. Now, the last piece to talk about is what do I do when my renal replacement therapy gets interrupted or they change the modality? This is a art, not a science, unfortunately. The way that I approach this is to think about how I would dose this specific patient with each of my modalities and then change my regimen when that prescription and that modality changes. Now, for our drugs that have narrow therapeutic windows like vancomycin and immunoglycosides, I would actually take into account other things like when their last dose was and not just change it without taking that into consideration. So for example, if I have a patient who's on CRRT and getting transitioned to IHD, if they just got a dose of vancomycin, I might actually allow two IHD sessions before I provide a supplemental dose. The converse is true as well. If I have a patient who's getting initiated on CRRT but just got their initial loading dose of vancomycin, I will allow anywhere from 12 to 24 hours before I provide the initial maintenance regimen while the patient's on CRRT. The last modality that we haven't really talked a ton about is PERT, so that Prolonged Intermittent Renal Replacement Therapy. How I will utilize and prescribe vancomycin in this setting is to look at the dialysis prescription. So at my institution, we often do a four-hour dialysis session plus maybe two or more hours of ultrafiltration. So if my dialysis component is anywhere from four to six hours, I'll just treat this like IHD dosing. But if that dialysate rate is going to exceed and you think anywhere from six to eight hours, I will provide an additional supplemental dose during dialysis or dose more frequently during that session and then go back to IHD dosing once the patient is off PERT therapy. So I know that was a lot of content. I hope I provided a little bit of insight and makes you guys feel a little more comfortable in dosing your medications when patients receiving RRT. Does anybody feel any more comfort in this area? I saw a little one. Okay, I'm getting a couple of hands. Okay. For those who didn't raise your hands, I'm going to put a shameless plug in, leverage your pharmacist, reach out to us, give us job security, if you will, and we will help guide your dosing in this disease state. But hopefully you can use a lot of these concepts and understand that this is not a one-size-fits-all approach for this population. That's all I got. Thank you. Thank you very much for that very nice talk. And finally, we're going to talk about Access, Membrane, and Antipovilation by Dr. Leonard Yesayan from University of Michigan. Hello, everyone. So yeah, the title of the talk is Access, Membrane, and Antipovilation. And I don't know, but we're going to try to do this in 15 to 20 minutes at the most. So the learning objectives are to provide an overview of essential points that guide providers in establishing optimal vascular access, provide an overview of CRRT circuit pressure parameters, and how they could be utilized to identify access dysfunction and membrane clotting or clogging, and provide an overview of anticoagulation strategies used in CRRT. Now, CRRT is often interrupted because of circuit and filter clotting. The most important reasons for the clotting are related to vascular access and insufficient circuit anticoagulation. So let's discuss some key points related to vascular access in the ICU. The two options of vascular access for renal replacement therapy are The two options of vascular access for renal replacement therapy in AKI, or acute kidney injury, are dialysis catheters or integration of the CRRT circuit into the ECMO circuit when that option is available to you or feasible to you in your institution. Now, the available options for dialysis catheter in acute kidney injury are short-term dialysis catheter. Also, we call these catheters acute catheters. And these catheters are uncuffed and non-tunneled. The other option is tunneled catheters. And in the ICU, most of our patients end up with short-term dialysis catheters. Now, the CADEGO guidelines suggest initiating renal replacement therapy in patients with acute kidney injury via an uncuffed non-tunneled dialysis catheter or an acute catheter rather than a tunneled catheter. And the rationale for these guidelines or recommendations is mainly due to the ease of placement and removal of these catheters at the bedside with little preparation or scheduling, unlike tunneled catheters. Short-term dialysis catheters have no cuff, as I said, and are non-tunneled. They are semi-rigid. What do we mean by that? They are rigid enough to allow for easy insertion, but soften once they are exposed to the blood or the body temperature, and this decreases the chances for trauma to the vessel walls. And this is achieved by using thermosensitive materials like polyurethanes. Now, acute catheters are designed to be in place for a short time, and they vary in shape, lumen, tip design, as well as their length. The proximal section can either be straight, curved, or pre-curved. The curved and the pre-curved extensions were developed to improve patient comfort when using an internal jugular insertion site. And be careful not to use these in femoral catheters because these curves will kink frequently if you use them in the femoral area. The lumens are configured in several patterns. The most common lumens are the double D, and triple-lumen dialysis catheters have an extra lumen and an extra port for administering medications, intravenous fluids, and many are designed also for power injection during radiology. Dialysis catheter tips come in different configurations, and there's no definite evidence regarding the effect of the different tip configurations on circuit life, but they all do the same thing. They are designed to minimize access recirculation, and they all have one thing in common, the arterial inlet is located at least two to three centimeters upstream from the venous outlet, as you see at the bottom, and this ensures that there is minimum recirculation and maximizes your dialysis efficiency. And in terms of length, they come in between 12 and a half centimeter to 24 centimeters. Now, what are the advantages and disadvantages of tunnel catheters compared to short-term dialysis catheters? Advantages include reduced risk of infection, mainly because tunneling reduces subcutaneous access of pathogens into the bloodstream. These catheters also provide mechanical stability against dislodgement since the cuff provides anchoring, and there are also less treatment interruptions with tunnel catheters, particularly at higher blood flows because their lumens are larger. The disadvantages of tunnel catheters include the need to move your patient to a procedure room, and it requires more time, and it requires more expertise. There's one small randomized control trial comparing femoral short-term dialysis catheters to tunnel catheters in 30 patients with acute kidney injury, and as you can see, the number of patients is too small to make any firm conclusions, but the number of catheter-related bacteremias and the number of interruptions were less frequent in the tunnel catheter group, and also the primary catheter patency was substantially longer for tunnel catheter. So coming to the next question, is there any role for tunnel catheters in the ICU? Yes, you may consider it in certain situations, and the CDC guidelines for prevention of catheter-related infections and the KDOKI guidelines, they both suggest that you can use a cuffed or a tunneled catheter for dialysis if a prolonged period of temporary access or prolonged time for dialysis is anticipated. For example, if you know if your patient is gonna be on dialysis for more than three weeks and you can move the patient to a procedure unit, then yes, perhaps you can start with a tunneled catheter. Now, the next question, what is the best site for dialysis access in AKI? The KDGO clinical practice guidelines for AKI suggest the following order of preference for central veins for dialysis catheter insertion. First choice is right internal jugular vein. Second choice is femoral vein. The third choice is the left internal jugular vein, and the last choice is the subclavian vein. One point to make is dialysis catheters in the subclavian vein are really not desired. They may cause central stenosis, limiting potential future vascular access creation in the epsilateral arm. So try not to do it unless it's the last resource. But you may be surprised as to why these guidelines recommend the femoral vein before the left jugular vein for an access site. And the recommendations mostly stem from the following two trials. The first study showed the rate of bloodstream infection and catheter-related colonization were not different between the femoral and internal jugular catheters. You can see this on your left. And the second study showed catheter dysfunction rates were highest with left internal jugular catheters. But two important caveats about these two studies. Well, in the first study on the left, if you look at the data, patients with BMI greater than 28 had higher rates of catheter colonization with femoral catheters than with jugular catheters. So a good reason to avoid femoral catheters when possible in this subgroup. I don't know about you, but I've never seen or I rarely see patients in the United States where I work with BMI less than 28. If we see that, it will elicit a malnutrition consult. Now, when it comes to catheter dysfunction, this is for the second trial, when it comes to catheter dysfunction, the tip of the catheter position matters, as I will point out in the next few slides. And this study did not report the catheter tip position. So it is possible that the tips of some of these left internal jugular catheters were not in an optimal position, and this could have contributed to the high rates of catheter dysfunction. So where should the tip of an acute dialysis catheter be positioned for optimal catheter function and to minimize catheter dysfunction? The tip of an acute internal jugular dialysis catheter should be in the distal superior vena cava or at the cavoatrial junction. So about two vertebral body levels below the level of the carina at the inflection of the right heart border with the SVC contour, must be also, and this is very, very important, it must be parallel to the long axis of the vein. Now, the tips of soft catheters, such as tunneled catheter, or even if you have an acute catheter that has a soft tip, they could be placed in the upper right atrium. And this is what we do with the tunneled catheters. They are placed within the right atrium because that provides them with more optimal function, but not too deep because you want to avoid touching the floor of the right atrium. Now, the tip of the femoral catheter should be in the inferior vena cava. So what are the optimal catheter lengths to have the tip positioned at or near the cavoatrial junction? You often read the following recommendations for catheter length. For right IJ, they recommend an acute catheter anywhere between 12 to 15 centimeters. For left IJ, 15 to 20 centimeter catheter. For femoral, 19 to 24 centimeter catheter. But patient height is not taken into consideration with these recommendation and may cause suboptimal tip placement, particularly with internal jugular catheters, and also with subclavian catheters, which we should be generally avoiding anyways. Now, the question is, should a six feet, six inches tall patient and a five feet, six inches tall patient have the same length of dialysis catheter inserted in their right internal jugular? Absolutely not. Now, Perez and his colleagues developed these simple formulas that you see using patient height and insertion site to better predict the length of the catheter needed to get the tip at the, or near the cavoatrial junction. These formulas were also later validated by another person and found to predict appropriate tip position in 90 to 97% of cases. So for right internal jugular catheter, the optimal catheter length is the height in centimeters divided by 10. For left internal jugular, it's the height in centimeters divided by 10 plus four. Now, and so in this case, the first patient will need a 20 centimeter catheter in their right IJ, and the second person will need a 15 centimeter catheter in their right IJ. Now, moving on to dialyzers, hemofilters, and membranes. So a dialyzer is basically made up of hollow fibers contained in a housing made of biocompatible materials. The housing contains inlet and outlet ports for blood and inlet and outlet ports for dialysate. A wide spectrum of filters and filter membranes are available in the market. Membranes in general are made up of either natural polymers or synthetic polymers. And membranes used in CRRT are almost exclusively synthetic, and synthetic polymers cause less complement activation than natural polymers such as cellulose. Moving on to CRRT circuit pressure. Knowledge of some basic information about these pressures is important as an intensivist, as they will let you know if you have access dysfunction or membrane issues coming up. Now, there are four circuit pressures that are continually monitored during CRRT. These include the access pressure, the filter pressure, the effluent pressure, and the return pressure. This pressure may vary with the device that you're using and the filter, but so you have to know your system. But access and return pressures inform you about catheter dysfunction. The transmembrane pressure and the drop pressure at the bottom, okay, that you can see are calculated pressures from data coming from the other measured pressures and inform you about membrane issues or problems. And I'll go over all of them very quickly. So access pressure is the amount of pressure used to pull blood from the central venous catheter to the machine at a set blood flow. Normal range in millimeters mercury is about half of the blood flow in milliliters per minute. It usually runs between negative 50 to negative 150 millimeter mercury for blood flows between 100 to 300 milliliters per minute. Now, it becomes more negative with higher blood flows and more resistance pre-blood pump. And it can be positive if you are connecting to a positive ECMO circuit. Positive pressure ECMO circuit. Now, when it is more negative than expected, and this is what you really need to know and you get calls for that, it usually indicates a problem and may lead to CRRT interruptions. It could be any of the following, a clottar kink in the CRRT access line, a clottar kink in the arterial lumen of the dialysis catheter, the catheter arterial side holes, like I showed you might be against the vessel wall on the side of the catheter, or the patient might be hypovolemic, we have a similar concept in ECMO when you hear about the ECMO chugging, or it could be secondary to increased intra-thoracic or intra-abdominal pressure. Some of them you can intervene and resolve the problem, that's why you have to know these. The return pressure, on the other hand, is the amount of pressure used to push blood back through the catheter into the venous circulation. The normal range is also about half of the blood flow, and it usually runs between positive 50 to positive 150 millimeters mercury for blood flows between 100 to 300 mL a minute. Now it becomes more positive with higher blood flows and more resistance post-pump, and again, when it's more positive than expected, and this is what you have to know, it indicates a problem, and it may lead to CRRT interruptions. It could be from any of the following, a clottar kink in the CRRT return line, clottar kink in the venous lumen of the dialysis catheter, the venous outlet of the catheter tip may be against the vessel wall, or the catheter could be inserted into an artery, or the tip could be perforating a vessel and is emptying into a hematoma. This, I'm not gonna go over this, you can have the slides, but this diagram shows you how to troubleshoot high access and return pressure alarms and how you can use it to identify the cause. Now, coming to two important pressure parameters that inform you about your membrane, the first one is the pressure drop. The pressure drop or the drop pressure is the difference between the filter and the return pressure, so the pressure difference across the filter where the blood is running, and it's an indirect measure of filter clotting or resistance. Now, the less the number of patent fibers because of clotting, the more the resistance of the membrane to blood flow, and therefore, you'll have more pressure drop from pre-filter to post-filter. You have to know your filter, at what range the pressure drop usually starts at, but if all of a sudden it increases or it doubles, you know that that filter is clotting and you might need to change the filter. Now, the transmembrane pressure is the pressure exerted on the filter fiber walls during ultrafiltration. It reflects the pressure difference between the blood compartment and the fluid compartment of the filter. During treatment, the permeability of the membrane decreases due to protein coating on the blood side, and this causes the transmembrane pressure to increase. Values greater than 250 millimeters mercury indicate the filter is clogging. We typically change the filter before the whole circuit clots and we lose blood. Moving on to anticoagulation for CRRT, why do we need anticoagulation? Well, we wanna maximize circuit life. We wanna minimize expense. We want to minimize blood loss secondary to circuit clotting. We wanna deliver the desired CRRT dose, and we wanna achieve the desired daily fluid balance goals by avoiding interruption. We also wanna decrease the nurse workload and you wanna keep your nurses happy. Now, anticoagulation can potentially be restricted to the circuit, in other words, we call it regional, or it could be systemic. The downside of systemic anticoagulation is the risk of systemic bleeding, and the two most common anticoagulation strategies are regional citrate anticoagulation and unfractionated heparin. I will briefly discuss both anticoagulation techniques and their risk and benefits. Now, the K-DECO guidelines recommend using regional citrate, like Javier said, rather than heparin in patients who do not have contraindications for citrate. Patients with contraindications for citrate are patients with absent liver metabolism, such as patients in short liver. Studies have consistently shown citrate improves filter life more than heparin. You should always try to use citrate if you can. The largest randomized controlled trial to date comparing regional citrate to heparin in CRRT enrolled 596 ICU patients across 27 medical centers. The study found filter lifespan was significantly greater in the citrate group compared to the heparin group. Medium filter life, 47 hours versus 26 hours, so a difference of roughly about 15 hours. And the citrate group also had significantly fewer major bleeding complications compared to heparin, 5.1% versus 17%. Now, a few words about citrate. Citrate has many properties making it desirable for use in CRRT. First of all, as you see on the top right side, it has small molecular weight and can go through the filter pore, so it's potentially dialyzable. And the mechanism of action is it chelates calcium in the extracorporeal circuit and prevents activation of calcium-dependent coagulation factors. Calcium is involved in the activation of many factors, including factor VII, IX, X, and prothrombin. Now, the anticoagulant effect of citrate in the circuit is measured by measuring the circuit ionized calcium. You want your circuit ionized calcium to be less than 0.4 at all times. And the anticoagulant effect is reversed by calcium infusion. Just let's go quickly over a representation of the circuit anticoagulation in this diagram. CRRT is infused into the access line of the CRRT circuit. As you see, it binds calcium and it lowers plasma ionized calcium level in the circuit. Most of the citrate calcium complexes are washed out in the waste fluid in that yellow bag at the bottom. The rest of the complexes go back to the patient. Now, if the liver is working, these complexes are metabolized by the liver and the calcium is released back into the circulation and the citrate is metabolized back into bicarbonate if the liver is working. Now, and calcium is infused into the circuit just before the blood goes back into the patient to reverse the low ionized calcium returning to the patient. Now, there's many protocols in the literature. The starting citrate varies by the type of the citrate and the protocol. And the maintenance citrate can be either titrated to achieve circuit ionized calcium, like I said, less than 0.4 to achieve anticoagulation. And in some protocols, the citrate rate is fixed, including in our program. So a few words about adverse consequences of citrate use. These include hypernatremia, which may occur because of the use of hypertonic citrate solutions. Hypo and hypercalcemia may occur because of inappropriate calcium supplementation if your calcium dosing is wrong. Hypocalcemia can also occur because of citrate toxicity in patients with liver dysfunction. Metabolic alkalosis can occur from citrate excess when the citrate is going back to the patient and being converted to bicarbonate at a high rate. And finally, metabolic acidosis can occur in shock state and severe liver dysfunction. Now, all of these complications, all of them can be avoided by protocol design. We use citrate even in patients with liver dysfunction with an exclusively citrate program. Now, two last slides. Unfractionated heparin is widely used for CRRT, and it inhibits factor 2A and factor 10A by potentiating antithrombin 3 by roughly 1,000 fold. Advantages of unfractionated heparin are that it's inexpensive, and it has a relatively short half-life, and is readily reversed with protamine if you really need to. Now, the disadvantages include the unpredictable pharmacokinetics resulting in dosing variability. What works for one patient might not work for another. And you can have heparin resistance in patients with low antithrombin levels. And patients may be at risk of developing, obviously, heparin-induced thrombocytopenia. And, of course, the heparin is going back to the patient, and it can cause hemorrhagic complication. So, in the last slide, although there are many existing CRRT protocol for systemic heparin anticoagulation, there isn't an optimal regimen. Usually, heparin is administered at the arterial side of the circuit as an initial bolus, then followed by a continuous infusion. And typical protocols target an APTT in the extracorporeal circuit between roughly 1.2 to 1.5 times normal, or 45 to 60 second, or an anti-10A level between 0.3 and 0.6 international units per hour. Most protocols measure the APTT or the anti-10 levels every six hours after starting treatment, or after changing the dose, and then every 12 hours if no further changes are needed. With this, I finish. Thank you all. Thank you.

continuous renal replacement therapy

CRRT

acute kidney injury

AKI

renal replacement therapy

medication dosing considerations

vascular access

anticoagulation

dosing

monitoring