Hello, good afternoon, good morning, and welcome to the 51st Critical Care Congress. This is a continuation of the Clinical Pharmacy and Pharmacology section's year-in-review, Focus on Infectious Diseases, Less is More. My name is Melissa Santibanez. I am a critical care clinical pharmacist and assistant professor at Nova Southeastern University College of Pharmacy in Florida. I have no real or potential conflicts of interest related to the subject matter of this presentation besides genuine interest in critical care infectious diseases. This session will aim to review the newest pharmacologic strategies related to infectious diseases, namely describing updates to the ID literature in the ICU related to, number one, the impact of active antipsudamonobetalactam use on bacterial resistance to other antipsudamonobetalactams, and number two, on the management of clostridioides difficile infections. Each of these selections of topics and literature is focused on a global theme of less is more as an antimicrobial stewardship strategy in the ICU. So the first topic to cover in this session is whether resistance to antipsudamonobetalactams confers success in the presence of resistance to other antipsudamonobetalactams. And this was a study published in Pharmacotherapy in 2021 by Lodis and colleagues. It was an exploratory hypothesis generating retrospective cohort study in the Kaiser Permanente group in Southern California across multiple sites in that network. The purpose of the study was to evaluate the effect of antipsudamonobetalactam resistance on certain clinical outcomes, and namely in patients with a Pseudomonas aeruginosa hospital acquired or ventilator associated pneumonia who were initially treated with a susceptible agent, betalactam agent. The four susceptible antipsudamonobetalactams defined and used throughout this study were piperacillin-tazobactam, ceftazidime, cefepime, or meropenem. Before moving into the specifics about the trial and what its findings were, it's important to note that in 2012, the Clinical Laboratory Standards Institute updated the breakpoints for Pseudomonas aeruginosa for piperacillin-tazobactam and the carbapenems, two of the four antipsudamonobetalactams that were included in this study. All study sites included adopted these revised breakpoints immediately. And so for all patients from 2012 through the end of the study period, these revised current breakpoints were utilized. And those breakpoints are reflected here in the bottom half of the slide. As you can see, for both piperacillin-tazobactam and the carbapenems, the breakpoint was lowered pretty significantly from what it was before. Patients were included in this study if they were adults admitted to the intensive care unit at one of the study sites with a monomicrobial Pseudomonas aeruginosa HAP or VAP over the seven-year time period. And if they received any one of the four susceptible antipsudamonobetalactams within two days of index culture. And index culture was either a respiratory or a blood culture. Polymicrobial infections, patients who died within two days and those with cystic fibrosis were excluded considering the intricacies and specific management of that particular infection. And only the first infection was included. So patients who developed secondary or tertiary infections, even within the same hospital stay, only the first infection was included as the index infection. And for data analysis purposes, the patients were stratified by the presence of antipsudamonobetalactam resistance on that index culture. So they were either stratified into a zero or a greater than or equal to one resistance group. And resistance was defined as either frank resistance or intermediate resistance on that culture. And the study had multiple primary outcomes, the main one being a composite outcome of in-hospital mortality or transition to hospice, but also looked at 30-day mortality and discharge to home. Now, a little bit over 550 patients were included in the study with well over three-quarters of them falling into the group that had no evidence of antipsudamonobetalactam resistance on index culture. And the primary outcome was observed, the composite outcome of in-hospital mortality or transition to hospice in about 30% of patients. Now, the unique aspect of this study's statistical analysis is that it utilized a technique called inverse probability of treatment weighting. And this is a technique that attempts to create similar groups out of dissimilar groups. So very much like a propensity score matching in order to determine whether a treatment or exposure was associated with a particular outcome or effect. So these groups were created through weighting, and then that removes the effect of any confounders that otherwise may have influenced the outcome. And each subject is weighted by the reciprocal of the probability of receiving the treatment that they actually received. And at the end of this process, a multivariable logistic regression was used to determine the association between antipsudamonobetalactam resistance and the primary composite outcome. So this figure depicts the percent standardized differences both before and after the IPTW treatment weighting analysis. On the y-axis, you can see a variety of variables that were otherwise considered to be confounders had the treatment weighting not occurred. And on the x-axis, the percent standardized difference. The open circles depict effects seen before the adjustment, and the closed diamonds reflect relationships observed after inverse probability of treatment weighting, after adjusting for those confounders. And it's crucial to note that after the IPTW analysis, the standard difference for all variables was defined to be less than or equal to 0.2 or 20% here on this graph. So it's important to see that all of the dark closed diamonds, they fall well below this 20% standardized line of standard difference, with the exception of the severity risk score called COPS, or comorbidity point score version two, which is based on 12-month patient data. And it's a comorbidity score that the higher the score, the more likelihood of patients having death due to that comorbidity. This was the only variable that fell out of the 0.2 or 20% standardized difference range. The other variables were clustered fairly closely together. There were no extremes observed after adjustment for confounders. So you're able to say that the propensity score matching used here was successful. And focusing on the primary analysis again, after the adjustment for confounders using inverse probability of treatment weighting, the odds ratio of patients experiencing that composite outcome of in-hospital mortality or transition to hospice was not statistically significant between groups based on resistance. But for patients who did have one or more resistance pattern observed, there was a statistically significant effect on 30-day mortality, with more patients dying within 30 days if they had at least one resistance pattern. The discharge-to-home outcome was assessed using a hazard ratio, and there was a statistically significant difference observed here, namely in that more patients with no evidence of resistance patterns were discharged to home. Now this table was taken from the supplement of the study, and it looks a little bit busy, but it also looks like an antibiogram. And it's a reflection of the individual beta-lactam resistance types that were observed in these isolates compared to what treatments the patients actually received. So what we can see here is that in this first column is the reflection of the antibiotic treatment that was received. And across the remaining columns is whether there was no beta-lactam resistance, one or two types of resistance patterns seen. And of the 553 patients and isolates, you can see that overwhelmingly more of them did not have evidence of any antiseudomonobeta-lactam resistance type. But of those who did have at least one beta-lactam resistance, the most common resistance was to meropenem. For patients who had two types of resistance patterns observed, the most common type was a resistance to both cefepime and piperacillin tazobactam. In conclusion, this exploratory analysis suggests that the full antiseudomonobeta-lactam susceptibility profile should be considered when selecting therapy for patients with a pseudomonas aeruginosa HAP or VAP. So now that we've reviewed the findings of this particular study, it's helpful to look at what clinical questions remain to be addressed and questions that were not fully addressed by this study as designed. So if you can type in your responses into the live chat box, you can go through this particular item first. What additional clinical questions related to antiseudomonobeta-lactam resistance were not addressed by the study? Was it effect on clinical cure rates, effect on non-pulmonary infections, effect on patients with recurrent infections, or all of the above? I'll give you a second to type into the chat. And quite honestly, it's all of the above. This was a study that was focused on strictly pneumonias and HAP and VAP. So strictly pulmonary infections, monomicrobial in origin. It excluded patients who had recurrent infections within that same hospitalization. And the outcome selected was more prognostic and mortality related as opposed to clinical. So looking at clinical cure rates and whether this specific knowledge of what is the full antiseudomonobeta-lactam susceptibility profile of a particular isolate, how that affects clinical cure rates for pneumonias, as was studied in this trial, but also beyond the pulmonary infections to see if this is an observation that fits the gamut of antimicrobial stewardship recommendations across the board. I would like to thank you for your responses to that question. And we'll wrap up this part of the discussion by looking at some limitations and potential for future expansion of this particular topic. So we just addressed the importance and effect of looking at a mortality-based outcome versus a more infection-related outcome when it comes to clinical effect of this particular strategy. The use and inclusion of just a single infection type. So it's not clear whether this antiseudomonobeta-lactam resistance strategy will have the same observed effect in patients who have polymicrobial infections, whether it's multiple organisms causing an infection in the same site or different organisms causing different infections across the body simultaneously. Additionally, the study did not determine, it was not able to determine the effect of the individual antiseudomonal drugs on these clinical outcomes of interest, especially of the newer agents like Avicaz or ceftazidime avibactam or Cervaxa, ceftolozanetazobactam. And we know that this is important because some of our patients already have an intrinsic resistance to Cervaxa and sometimes Avicaz as well, even though they have never been exposed to these agents before. So this will affect our less-is-more type of stewardship mentality and de-escalating therapy in the future. The potential for confounding in that we can infer that patients who had the presence of at least one type of resistance to antiseudomonal drugs had a higher severity of illness. And this was confirmed by the fact that those patients who did not have any resistance patterns were significantly more likely to go home within 30 days, as opposed to those who did not. And finally, the update to the pseudomonas breakpoints that was addressed before and how now in the nearly 10 years since those updates were made, how that is affecting clinical outcomes, that remains to be seen. Okay. And with that, we will move into the second focus of today's session, which is the 2021 focused update to the management of Clostridioides difficile infection. This clinical practice guideline focused update is a conjunction of both the IDSA and SHEA and a panel representing both organizations. And it was aimed to update the 2017 C. diff treatment guidelines, especially for Fidaxomycin and Bezotuximab. So these focused updates are looking more at the standpoint of recurrent infections and what is the role of some of these adjunctive therapies. So because this was a focused update to a practice guideline, I arranged the sub areas of this topic into the actual content updates that the guideline presented. The first of which having to deal with initial C. difficile episodes and what is the role of Fidaxomycin as opposed to Vancomycin. This was one of the major areas of update in the 2017 guidelines. And the panel experts found with moderate certainty of evidence that Fidaxomycin is recommended over Vancomycin PO. However, Vancomycin PO remains a suitable alternative. Before moving into the next set of updates, because they focus on recurrent infections, thought it good to ask a question related to what are these risk factors for C. diff recurrence. So if you can type your answers in the chat box for this question, we'll go through some of these options. Which baseline characteristic is a risk factor for C. difficile recurrence? Is it advanced age over 65 years? Is the earliest use of Fidaxomycin having severe C. diff on the initial episode or having an initial episode requiring mechanical ventilation? There are actually two correct responses here. The first being advanced age and the second being having a severe initial episode. And thank you for your responses to that question as well. It leads us into C. diff update number two. For those individuals with a recurrent infection, should Fidaxomycin be used versus Vancomycin PO? And the recommendation was, based on a low certainty of evidence, that Fidaxomycin is recommended over Vancomycin PO. So now it's recommended for the initial episode and for this first recurrence. Vancomycin PO, whether standard dosing of 125 milligrams POQ6 or as a pulse dose regimen, remain acceptable alternatives for that first recurrence. And then there are additional recommendations for second recurrences and beyond. And the final category of C. diff related updates also looked at or focused on recurrences, but now trying to determine the role of beslatuximab, which back in 2017, that guideline revision from the IDSA mentioned beslatuximab for the first time and having a role in preventing further recurrences. But it was not quite clear at that point what exactly was the niche for beslatuximab and at what level of recurrence is it most effective. So the question asked was, in patients with a recurrent C. diff infection, should beslatuximab be added to the standard of care antibiotics, whether Fidaxomycin or Vancomycin PO, as opposed to using the standard antibiotics alone? And the recommendation was in favor of beslatuximab adjunctive to the standard of care antibiotics, although this was based on a very, very low certainty of evidence. And it isn't in every patient. It's in those who have risk factors for C. diff recurrence in the next six months. And those risk factors are, again, that advanced age above 65 years, the presence of a severe infection, which is defined as a white blood cell count greater than or equal to 15,000, or a serum creatinine greater than or equal to 1.5 milligrams per deciliter. And finally, patients with a history of immunosuppressive drug use or immunosuppressive conditions, including chronic steroids, patients with transplant or anti-rejection drugs, and other conditions. So to start putting all these recommendations together, this table summarizes the focus guidelines, recommendations for initial and recurrent infections, both the first and second and thereafter, and for fulminant C. diff. The initial episode is recommended to use fidaxomycin over vancomycin PO. And for the first recurrence, fidaxomycin monotherapy, again, is recommended over vancopo. And if that patient, since it's the first recurrence, if they have the risk factors for recurrence, there is a recommendation to add on IV beslatuximab one dose in addition to that standard of care antibiotic. Second recurrences and above can consider using fidaxomycin monotherapy again with the beslatuximab if those recurrence risk factors are there. And these patients have already had two recurrences, if not more. So most of them are likely going to require use of beslatuximab. But then there's also recommendations here for initial use of vancomycin tapered dose regimens and fecal microbiota transplant, which is recommended to be used when patients have at least had two recurrences or three total infections with C. diff. So these focused update recommendations promote a less is more stewardship philosophy by streamlining the treatment recommendations based on evidence for initial episodes and at least the first recurrence to be consistent with fidaxomycin in all cases, as opposed to having multiple therapies. Again, there is a potential to add on adjunctive therapies once patients have at least one recurrence based on their likelihood to have a recurrence again. But the limitations with these recommendations mainly center on this distinction between a recurrence versus a treatment failure. And when a prior episode is not completely or thoroughly treated and then leads to a follow up episode, which is now a recurrence. So what is the effect that these two types of occurrences have on one another? There's also limited data on beslatuximab's efficacy and benefit when used with fidaxomycin. So considering that fidaxomycin is now the preferred agent for initial episodes, as well as first recurrences, adding beslatuximab, the full benefit remains to be determined. And on that note, the impact of having multiple adjunctive strategies for patients who are having recurrent infections, including beslatuximab, but also fecal microbiota transplants for those who have at least two recurrences. And of course, the ever present cost consideration, considering the expensive acquisition cost of beslatuximab and even fecal microbiota transplant compared to vancomycin PO or even in some for some institutions, fidaxomycin. So this concludes the infectious diseases less is more portion of our CPP year in review session. And I would like to thank you for your attention. My email address is provided there. Should you have any additional questions? And I look forward to the live chat discussion during Congress. Thank you all for your participation. Hello, everyone. My name is Keaton Smitana. I am a neurocritical care pharmacist at the Ohio State University in Columbus, Ohio. And today, during this portion of the year in review, we will be discussing updates and nutrition for the critically ill. I have no financial conflicts of interest to disclose, and these are the two studies that we'll be highlighting during this discussion and kind of leading to some of the questions that we'll be posing on how we approach general nutrition in our critical care patients. So when it comes to nutrition, it's not or shouldn't be a surprise to most of you that we often fall short of the goals that we are setting out to achieve. And this has been shown time and time again in studies that have been published. In this specific study, this was our own experience in a neurocritical care unit. And we looked at the first seven days of general nutrition that a patient received, and we compared that to indirect calorimetry data. We would receive indirect calorimetry within 48 hours, and then we extrapolated the daily resting energy expenditure for the first seven days of their stay to look at the differences. And this was in 91 neuro ICU patients. And to orient you to the graph, zero, or where the blue box is pointing, would mean that the K-cals received within the first seven days of their stay was equivalent to what we extrapolated out as their seven-day energy expenditure needs. As you can see, it's pretty evident that for a majority of the patients, we fell short, not often being anywhere from 5,000 to 10,000 caloric deficit within seven days. So our first study that we'll look at is an improvement in protein delivery for critically ill patients requiring high-dose propofol therapy and oral nutrition. And this study was conducted between February and October of 2018. This was a retrospective single-center study, and they evaluated first the amount of calories provided by propofol and internal nutrition therapy. And then secondarily, they compared protein intake using a modified approach of protein supplementation to just conventional internal nutrition formulas when given without protein boluses. So on the bottom left, if you look at their modified internal nutrition approach with protein supplements in terms of what they were using for baseline formula, it was dependent upon the injury severity score with a cutoff of 20. So those with less than 20 received what they labeled as a very high-protein formula, and those greater than or equal to 20 had a high-protein formula there. Their inclusion criteria were patients greater than or equal to 18 years old that had sustained a TBI, admitted to their trauma ICU, who also had a nutrition support service consult. Additionally, they had to have received propofol for greater than or equal to two days. They excluded patients that had died within seven days, received parental nutrition, or had inadequate documentation. Again, this is just to highlight on the left the differences in the nutrition therapy that was given between a very high-protein formula and a standard protein formula. And it's important to note that in their intervention groups, both used protein supplementation. On the right yellow box there, you can see their nutrition targets was based off of BMI. So those with a BMI less than 30, their goal caloric energy they gave was 30 to 32 kcal per kilo per day with a goal protein of 2 to 2.5 grams per kilo per day. And they labeled patients as being overfed if they were over 32 kcal per kilo per day. And the BMI greater than or equal to 30, you see there that they based it off of ideal body weight with a kcal goal of 22 to 25 and then a protein goal of 2 to 2.5 grams per kilo per day. And that group had overfeeding labeled as greater than 25 kcals per kilo of ideal body weight per day. From a results standpoint, they screened 118 patients and excluded 67 with most either having died within seven days, having inadequate documentation, or most of the 20, about 20 patients not receiving propofol with a total inclusion of 51 patients. To orient you to the graph that you see here, on the y-axis is their caloric intake, and on the x-axis is their trauma ICU day. They did not include day one as it could have just represented a partial feeding day as they titrated up. The black bar is total calories received. The lighter gray is their internal nutrition calories, and the darker gray bar is their propofol calories throughout days two to seven. When you look at the characteristics of propofol, they found that patients received a median of 356 kcals per day, and that would equate to a rate of propofol of around 27 mics per kilo per minute in an 83-kilo patient, just to put it in some other terminology. Then on the internal nutrition characteristics, they looked at day two and day seven. As you can see there, day two had a median of 7 kcals per kilo per day versus day seven having 16 kcals per kilo per day. With this graph, they looked at the protein that was delivered. The y-axis is the grams per kilo per day of protein intake. The x-axis, again, same time period. As you can see there, they have the different bars labeled as A, B, and I think day two on the far left, that dark gray bar should have been C. They equate to the actual intake being the black bars that were labeled with A, and then the various projected intakes based on if you used a high-protein formula, which would be B, and then a standard protein formula, which would be C here. They found that when they compared protein intake using their modified regimen of supplementation to the very high-protein formula, that it increased protein delivery of about 24 to 38 percent. Then when you compared their modified regimen of protein supplementation to a standard protein, the internal nutrition formula was about two-fold higher. It is important to note if you look across the graph here that it takes a couple of days to even get up to a gram per kilo per day, and they weren't necessarily attaining their target of 2 kcals per kilo per day throughout the time period. In conclusion, the study of supplemental protein as liquid protein boluses improved protein delivery without the risk of overfeeding when modifying internal nutrition rates to maintain their caloric needs. A limitation, as I said just a moment ago, was that their protein delivery still fell short of their goals. This is likely due to withholding internal nutrition for various regions. This is surgical and diagnostic procedures. Lastly, just in general consideration, when we're thinking about protein delivery as a whole, we don't necessarily have a reliable biomarker that can tell us what someone's protein needs are, such as indirect calorimetry giving us resting energy expenditures. This is something to keep in mind moving forward, that instead of just having a range of 2 to 2.5, maybe we could individualize this to the patient's protein needs and then see how this impacts long-term outcomes. A polling question, and I believe this should be on your pop-up in the chat area for you to answer. This might also be on Twitter for those that are on Twitter if they want to answer and follow along there. What would you change with your current practice for patients who are receiving propofol to attain macronutrient goals? Answers being no change, so I don't modify internal nutrition based on propofol rates. No change, I don't modify internal nutrition to attain protein goals that we've set out. Number three being I'll start using supplemental protein to attain these protein goals that we're setting out in the beginning of their therapy. And four being I'll start using high protein formulas. Let's give everyone a few seconds to kind of answer these in the chat. Okay. So, our next study, the FEED-MORE study, is a volume-based feeding enhances internal delivery by maximizing the optimal rate of internal feeding. This was published in J-PIN in 2020. Their methods for this study was they looked at patients between September of 2015 to March of 2017. This was a retrospective single-center quasi-experimental study with their primary aim being to evaluate the mean percentage of total energy delivered by internal nutrition until seven days ICU transfer or removal of the feeding tube, or they received an oral diet. Secondarily, they looked at the mean percentage of total protein, the percentage of patients meeting 80% of their energy and protein goals, which is a goal recommendation in the Aspen critical care guidelines for nutritional delivery. They also looked at time to goal rate, days of ventilation, and then ICU and hospital length of stay. On the safety standpoint, they looked at the rates of patients who had elevated glucoses, which they labeled as greater than 250 during their catch-up periods for those that were on the rate-based versus volume-based, and then they looked at gastric residual volumes over 400, and then just a general discontinuation due to intolerance of the volume-based feeding protocol. On the bottom left, if you look at their rate-based feeding, they based their nutritional goals, so their caloric needs and protein off of the Aspen guidelines. They would start at 10 to 20 mLs per hour, advanced every six to 24 hours, and this was per provider. The volume-based feeding group, they started slightly higher at 30 mLs per hour, and they advanced to goal at four hours with a daily catch-up phase on day two, and when they were doing the volume-based feeding, their maximum rate that they would go up to was 150 mLs per hour. They included adults in the medical and neurosurgical ICU, and between the years of 2015 to 2016, they did rate-based feeding, and then 16 and 17 after a washout period, volume-based feeding, and excluded those that received perinatal nutrition or had an ICU length of stay of less than 24 hours. They screened 331 patients during this time period, and a majority of the excluded patients were just in ICU length of stay, less than 24 hours, including 189 patients, 100 being in the rate-based group, 89 in the volume-based group. When you look at their results, so the total energy delivered, 100% was attained with the volume-based feeding that they were wanting to give, and you see a 25% less attainment of total energy delivered in the rate-based feeding group. The total protein delivered was 19% lower in the rate-based feeding group at 68% versus 87%, and those who attained 80% of their goal energy, which, again, is the Aspen guideline recommendation, you see a difference of nearly 30% with only 42% in the rate-based feeding group versus 71% in the volume-based feeding group, and then from a goal protein standpoint, you see a 23% less attainment in the rate-based feeding group, as you see there with 34% versus 57% attaining those goals. From an efficacy standpoint, the time-to-goal rate, which isn't too surprising given that the difference was based off of a increase over 6 to 24 hours in the rate-based group versus advancing to goal at 4 hours with volume-based feeding, was 13 hours versus 7.7 hours. If you look at the chart on your right, they looked at the mean cumulative caloric deficit by day, and the yellow line is the volume-based feeding group, which had that catch-up period versus the blue line, which is the rate-based feeding group, and the yellow line, as you can see, hovered around 1,000 kcal's deficit over the time period, but you see a precipitous drop with the rate-based group out to 7 days. From a safety standpoint, so one thing that's come up that's discussed is the risk of hyperglycemia in patients that you're bolusing essentially to try to get them to their target daily calories for the day, but they only saw a 10% increase in hyperglycemic episodes during the catch-up periods of those on the volume-based feed group. When they looked at gastric residual volume incidents, which again, greater than 400 mLs, they saw a 1.4% increase in those in the volume-based feeding group. ICU length of stay was a day shorter in those with volume-based feeding, so 5 versus 6, and then in terms of hospital length of stay, they actually saw a shorter length of stay in those in the rate-based feeding group of 16 versus 20. In conclusion, volume-based feeding significantly increased the energy and protein delivery in a safe manner. We saw there was overall in the volume-based feeding, about 16% of patients during that catch-up period had hyperglycemic episodes over 250 and a relatively small rate of gastric residual volume being over 400. The rate-based feeding group's rate of titration was not standardized, but the goals were consistent with the Aspen Guidelines, so again, going back to providers saying how to titrate over time in the rate-based feeding versus volume-based feeding group. A limitation and consideration just in general about the collection was there was no data collected on the use of opiates or prokinetic agents, nor severity of illness, which may impact GRV, length of stay, et cetera. And just in general overall, you know, further studies are necessary evaluating patient-specific needs, and if outcomes differ, if we attain these goals, this 80% goal set out by the Aspen Guidelines versus those that might be slightly under in the early part of their critical, their ICU stay. So our polling question for this is, does your institution use volume-based feeding in patients receiving internal nutrition? Again, this should pop up in the chat with, yes, all patients receive volume-based feeding in our institution. Yes, but only in select patients do we use volume-based feeding. Number three, we do not use volume-based feeding. Number four, we do not use volume-based feeding, but based off of this study and some other considerations, you may start using this moving forward in select patients. Okay, I will say at our institution, we do this in select patients, specifically in our burn population, but given the initial study I shared with you all looking at our caloric deficits and how it builds over the first week, this is something that we're considering trialing in our neuro ICU and seeing if that helps attain our goals for caloric needs and then hopefully protein needs as well. I'd like to thank my year interview mentors and also the CPP program committee members. And finally, just some general thoughts to help maybe guide some discussions if you're able to answer on Twitter or in the poll here and we could try to respond. When we think about supplemental liquid protein, it can help us get closer to attaining our protein goals, but as we saw in the study, it didn't actually meet the goals they set out. So some general thoughts, maybe should supplements be used as a bridge until goal and all nutrition is reached? So depending on how long it takes for you to titrate to goal should you be using protein supplementation? And then the second question is how much protein is too much? So in general, the thought is the body can absorb around 10 grams per hour of protein or 20 to 25 grams per sitting. So how many packets will you use per day and how do you separate that out? Mostly, I don't see us going beyond two packets of 15 grams of protein. So a total of 30 grams, three times daily. And then on the volume-based side, if we're gonna consider this in the ICU, what barriers would you need to overcome to implement this practice? So obviously there would be a lot of education on how to attain these goals. What part of the shift would you try to attain or try to implement this change and reach your goals? And is there anything from the medical record side of thing that you need to do? So how can we maybe leverage technology to improve nutrition delivery? So what we did in the last few years, which has been a major help, was that we were able to actually track internal nutrition into our continuous, basically where our grips would show up on our MARs. So we're able to go back and look when it was held and then also look at total volume received. So that's been a better way to at least kind of have a general sense of what we're, or how close we're getting to our goals. So thank you for listening. And I look forward to interacting with you on the chat box. Hi, my name is Patrick Wietoszewski and I'm a pharmacist in the cardiothoracic surgery and ECMO program at Mayo Clinic. I'll be discussing the cardiac surgery and cardiology year in review updates. I wanted to take a moment to thank the CPP section and the CPP programming committee leadership for inviting me to do this talk. It truly is an honor and privilege to speak to you all today. I have no relevant disclosures related to this presentation. Today we'll evaluate the evidence for updates in the management of critically ill cardiovascular surgery in cardiology patients. Extracorporeal membrane oxygenation or ECMO is a form of temporary mechanical circuitry support that is deployed in refractory cardiopulmonary failure. ECMO is a very resource intensive intervention. And over the past several decades, it has been gaining a lot of interest as a rescue option until underlying pathologies are treated or organ transplantation can occur. Plotted here in the purple bars are the cumulative number of ECMO centers worldwide. These are data from the Extracorporeal Life Support Organization. You can see up until the late 2000s, the number was steady around 100, but appear to take off in the 2009, 2010 time period. And this is likely following the surge in ECMO use during the H1N1 influenza pandemic. These continue to rise and in 2020, there were over 500 ECMO centers worldwide. That's an over 400% increase from the preceding 10 years. And concurrently, I've also plotted for you the orange line, which is the number of new papers indexed in PubMed that are relevant to ECMO anticoagulation, which has also seen a very similar rise over this time period. And in 2020 alone, there were over 200 new ECMO anticoagulation papers indexed in PubMed. And this increasing interest is rightfully so as normal physiologic coagulation is disturbed in patients on ECMO. With the introduction of the ECMO circuit, circulating blood is exposed to a large surface area of foreign non-endothelialized surfaces. And these include the large bore cannulas, the mechanical pump and membrane longer oxygenator. And what ensues is a systemic inflammatory response, activation of cytokines and initiation of the extrinsic coagulation pathway. And if there's severe cardiac failure or ventricular standstill, there's also a risk for thrombus formation. And this is especially true if the left heart is not adequately offloaded. The mechanical pump also contributes to coagulopathy through high shear forces that facilitate uncoiling of large von Willebrand multimers, increasing their susceptibility to cleavage. These issues are all compounded by the underlying diseases and indications for going on ECMO that might also inherently have their own coagulation imbalances. And what results is a state of platelet and coagulation factor consumption, excess activation of fibrinolysis and a progressive thrombocytopenia. Taken all together, anticoagulation during ECMO is very complex and it requires a very fine balance to mitigate the prothrombotic potential while minimizing hemorrhagic complications. And the clinical consequences from coagulopathies are the most common adverse events that ECMO recipients experience. On the left-hand side are adverse events separated by respiratory ECMO on top and cardiac ECMO on the bottom. And these are data from the Extracorporeal Life Support Organization Registry of nearly 80,000 ECMO runs. And I've highlighted all of the complications related to thrombotic events, including pump malfunctions, oxygenator failure and stroke, as well as bleeding complications at the site of the cannula, surgical sites, as well as pulmonary and CNS bleeding. Now, all of these coagulation-related events account for the large majority of adverse events ECMO patients experience, and they are highly consequential. Shown on the right are data from Mike Mazzeffi's group in Maryland, where they found a nearly two-fold lower survival at 90 days in patients who experienced bleeding events during ECMO. If you are listening to this session live, I'd love to hear your thoughts and experiences with anticoagulation. In adults on ECMO, which of the following would you recommend for hemostatic management? Heparin infusion? Bivalrutin infusion? No anticoagulation? Or would you like to hear some more information to make a decision? Please feel free to enter these in the session chat box. Now, historically, heparin has been monopolized as the anticoagulant of choice during ECMO, and this is largely extrapolated from its familiarity in the setting of cardiopulmonary bypass. However, heparin does depend on antithrombin to exert its pharmacologic effect. It also has the potential for immunogenic platelet sequestration and thrombus formation through heparin-induced thrombocytopenia. And it also interacts with multiple different plasma proteins, and this leads to unreliable and inconsistent dosing. Bivalrutin is a direct thrombin inhibitor and has been gaining increasing popularity as an alternative agent for anticoagulation during ECMO. Bivalrutin has a rapid onset, short half-life, a low incidence of thrombocytopenia, a pharmacologic effect that is independent of a cofactor, and it also has reversible thrombin binding, and this has been proposed to lead to less bleeding. And today, we'll discuss two new papers that were published in Critical Care Medicine in the summer and fall of last year that compared heparin and bivalrutin during ECMO. Ryan Rivasecki's group at the University of Pittsburgh converted to a primary bivalrutin-ECMO program back in 2017. They performed this retrospective cohort analysis of nearly 300 VV-ECMO runs before and after this conversion. Now, their cohort was young with a median age of 49 years, 60% of them were male, and these were predominantly medical admissions. There were 162 patients in the heparin group and 133 patients in the bivalrutin group. And indications for ECMO are listed here, and as you would expect, they are all respiratory indications. Most of them had acute respiratory failure, and this was more common in the bivalrutin group than the heparin group, whereas pre-lung transplant was a more common indication in the heparin group as compared to bivalrutin group. And what they found was an over threefold higher rate of major bleeding events in the heparin group at 41% compared to just 12% in the bivalrutin group. Similarly, the incidence of circuit thrombosis was higher in the heparin group at 33% compared to just 17% in the bivalrutin group. And this also held true when they adjusted for the duration of the ECMO run in terms of circuit thrombosis per day of ECMO. Shown on the right is the adjusted Cox regression analysis they performed that included covariates for age, sex, admission type, presence of lung transplant, and exposure to anticoagulation in the first 24 hours. And in this, they found that the bivalrutin group was significantly less likely to develop a thrombosis compared to the heparin group during their entire ECMO run. And what was very interesting was the amount of transfusions these patients received. You can see here on the left-hand side that the heparin patients also received significantly more blood transfusion than the bivalrutin patients. The heparin patients received over two and a half liters of red cells whereas the bivalrutin patients were just under one liter. And this was also true to a lesser extent with plasma and platelets. And although the duration of the ECMO runs were comparable, the overall lengths of stay did not differ. There was also no difference in the ECMO survival rate, but more patients in the bivalrutin group were alive at one year after ECMO separation. Now, the second paper we'll review is from Troy Seelheimer's group in the Mayo ECMO program. They performed a retrospective cohort study of adult and pediatric ECMO patients receiving bivalrutin or heparin anticoagulation. They had 333 adults that were included, and most of these were over the age of 50 years. 65% of them were male, and 40% of them were on continuous renal replacement therapy. These patients were predominantly recipients of VA ECMO in the post-cardiotomy setting. And accordingly, the majority of these were central ECMO. Similarly, the 89 included pediatric patients were predominantly infants, and they were also receiving VA ECMO in the post-cardiotomy setting, as well as a large amount of eCPR. A quarter of these pediatric patients were also on continuous renal replacement therapy as well. They found no differences in the primary composite endpoint of circuit intervention and oxygenator or pump change-out rates in either of the adult or pediatric groups. However, as you can see in the adult groups, the other circuit interventions that were unspecified, rates were greater in the adult heparin group compared to the adult bivalrutin group. And also, the hospital mortality rate was higher in the adult heparin group than the bivalrutin group at 53% versus 38%. Pediatric patients that received bivalrutin also had less transfusion requirement in the first 24 hours of ECMO. Otherwise, there were no differences in transfusions amongst the groups. Shown here is the multivariable model that they fit to assess the effects of anticoagulation choice on outcomes. The lower hospital mortality rate that we just showed in the adult bivalrutin group that was found in the crude analysis was also maintained in the multivariable analysis. Otherwise, there were no other major differences that were identified between the groups. So overall, from these two new papers, it appears that bivalrutin is emerging as an alternative for primary anticoagulation management in ECMO patients. And as discussed before, there are many scenarios that bivalrutin provides a favorable pharmacologic profile compared to heparin. This newer evidence supports less bleeding and thrombotic complications when bivalrutin is used, as well as potentially fewer transfusion requirements compared to heparin in select patients. Now, in terms of some limitations, the Rivosecki paper was exclusively in VB-ECMO patients with a very large predominance of lung transplant recipients. And also, the Seelhamer paper was predominantly central VA-ECMO. And so the generalizability of each of these studies was quite limited to a broad population of ECMO recipients, given their narrow scope. Additionally, both centers performed a program-wide switch to bivalrutin during the study time period. And in both of these papers, the earlier half of the study was predominated by heparin recipients. Now, there might be some unaccounted-for confounding that related to the evolution of ECMO care over this time period, and the increase in the program's experience temporally as time went on. And these certainly could have influenced the results. Lastly, the intensity of the anticoagulation and the amount of pausing that occurred during ECMO runs, potentially for bleeding or procedures, were not reported. So the optimal timing and dosing practices of these anticoagulants still remain unclear. Once again, if you're listening to this session live, please enter your response to this question in the session chat box. A 37-year-old male with refractory hypoxemia secondary to influenza pneumonia was cannulated for VV-ECMO. CT scan of the chest demonstrates bilateral pulmonary emboli. Which of the following would you recommend for hemostatic management for this patient's ECMO circuit? Heparin infusion, bivalrutin infusion, or no anticoagulation? In conclusion, hemostatic management during ECMO is very complex. It requires a fine balance of delivering anticoagulation to prevent thrombus deposition while minimizing hemorrhagic complications. There is an increasing experience and body of evidence with the use of bivalrudin as a primary anticoagulant during ECMO. Further studies are necessary to better understand the impact of bivalrudin on the totality of ECMO management and outcomes in ECMO recipients. I wanted to thank you all for your attention and attending today.

management

critically ill

cardiovascular surgery

cardiology patients

anticoagulation

extracorporeal membrane oxygenation

ECMO

bivalirudin

heparin