Good afternoon, and welcome to today's Journal Club Spotlight on Pharmacy webcast, which is supported by the Society of Critical Care Medicine's CPP section. My name is Christine Groth, and I'm a Clinical Pharmacy Coordinator for Adult Critical Care in Emergency Medicine at the University of Rochester Medical Center in Rochester, New York, and I will be moderating today's webcast. A recording of this webcast will be available to registered attendees. Log into myscm.org and navigate to the My Learning tab to access the recording. Thank you for joining us. A few housekeeping items before we get started. There will be a Q&A after each of today's speakers. To submit questions throughout the presentation, type into the question box located on your control panel. You will also have the opportunity to participate in several interactive polls. When you see a poll, simply click the bubble next to your choice. SCCM provides the following disclaimer. This presentation is for educational purposes only. The material presented is intended to represent an approach, view, statement, or an opinion of the presenter, which may be helpful to others. The views and opinions expressed herein are those of the presenter and do not necessarily reflect the opinions or views of SCCM. SCCM does not recommend or endorse any specific test, physician, product, procedure, opinion, or other information that may be mentioned. And now I'd like to introduce your speakers for today. Each will give a 15-minute presentation followed by a Q&A. Our first presenter today is Jessica Arabi, and she's a PGY-2 critical care resident at Froedtert and the Medical College of Wisconsin in Milwaukee, Wisconsin. Our second presenter is Suhaila Hamoud, a PGY-2 critical care resident at St. Joseph Mercy Oakland in Pontiac, Michigan. And our third presenter is Lane Rayhart, a PGY-2 critical care resident at Prisma Health Richland, University of South Carolina in Columbia, South Carolina. And now I'll turn things over to our first presenter, Jessica Arabi. Thank you for the introduction, and good afternoon, everyone. I'm going to be presenting on the article entitled, The Neuroprotective Effect of Quetiapine in Critically Ill Traumatic Brain Injury Patients. I have no conflicts of interest to disclose. And starting off with some background, as we know, traumatic brain injury, or TBI, is a major cause of morbidity and mortality. Furthermore, secondary injury results from the disruption in cellular function and an imbalance between oxygen supply and demand. There have been previous studies conducted in rodent models demonstrating that quetiapine was able to maintain cognitive recovery and may present as a safer alternative for TBI-induced agitation compared to typical antipsychotics such as haloperidol. Furthermore, quetiapine showed maintenance of blood-brain-barrier-tight junction integrity, which may control inflammation and secondary injury, which we know is a major cause of morbidity and mortality in these patients. However, there is no current guideline recommendations for the treatment of TBI-induced agitation. The authors of this study hypothesized that the administration of quetiapine is associated with improved neurological outcomes in TBI patients. This study was designed as a single-center retrospective cohort analysis of patients admitted to the Beth Israel Deaconess Medical Center in Boston, Massachusetts. They pulled information from a large collection of databases from patients admitted to the ICU from 2001 to 2008. They included adult patients that were diagnosed with an isolated TBI, which they defined as an extracranial abbreviated injury scale less than 2. Patients also had to be admitted to the ICU for greater than 48 hours. They excluded patients with any withdrawal of life-sustaining treatment, do not resuscitate, or do not intubate orders. They also excluded patients if they received any non-quetiapine antipsychotic during their hospitalization. In terms of their statistical analysis, they calculated their power based on their sample size and they assumed that the P equals 0.05 to be statistically significant and determined that the calculation was a small effect size based on mortality difference. They calculated their power to be at about 75% in order to detect a difference in primary outcome. They did a 1 to 2 propensity score matching based on baseline characteristics in order to account for potential confounders. They matched patients based off of baseline characteristics as well as their method of injury, whether it was blunt or penetrating trauma. They also matched patients based off of presenting ED vitals as well as any interventions such as intubation or neurosurgical interventions. Additionally, they also included matching patients based off of medications that they received for intracranial pressure control as well as agitation. Furthermore, they conducted a subgroup analysis for patients who underwent ICP monitoring as well as three univariate analyses for the outcomes based on the number of doses patients received. So they categorized this based off of one dose, greater than one dose, or no doses received. Based off of age categories as well as severe TBI, which they defined as a Glasgow Coma score of less than or equal to 8. After patient selection, there was almost 60,000 patients included in this database and 5,500 of those had a diagnosis of traumatic brain injury. After exclusion, they had 890 patients, 116 that received quetiapine and 774 had no quetiapine. After their matching, they had a final sample size of 116 for quetiapine and 232 received no quetiapine. In terms of their outcomes, their primary outcome looked at in-hospital mortality as well as discharge Glasgow Coma score or GCS. Their secondary outcomes were skilled nursing facility disposition and ICU length of stay. Now to highlight the results, I wanted to go over a few key cohort characteristics. The majority of patients were around 65 years old with the majority being Caucasian males. The median quetiapine dose was 50 milligrams with a mean number of doses of three. Admission GCS was a median of nine and about 54% of patients sustained a moderate TBI, which they categorized as a GCS between nine and 12 and 27% had a severe TBI. Moving on to the results of their primary outcome, I wanted to highlight the results for mortality and discharge GCS. For mortality, they saw about a 17% rate in the quetiapine group versus 27% in the no quetiapine group. This was about a 10% reduction that was found to be statistically significant. In terms of their discharge GCS, the quetiapine group had a GCS of 12 versus 11 in the no quetiapine group. Again, this was found to be statistically significant. However, in terms of their secondary outcomes, their ICU length of stay as well as the skilled nursing facility disposition had no difference between the quetiapine group and the no quetiapine group. For their subgroup analysis of patients that received higher quetiapine doses, they conducted a multivariate regression analysis to determine the independent effect that quetiapine had on intracranial pressure and cerebral perfusion pressure. And what they found was a statistically significant reduction in the intracranial pressure per milligram of quetiapine. Similarly, they saw a statistically significant reduction, sorry, statistically significant increase in cerebral perfusion pressure per milligram of quetiapine. In terms of their univariate analysis for outcomes in patients with severe TBI, they saw similar results to their primary and secondary outcomes. I wanted to highlight mortality as well as discharge Glasgow Coma Score. For mortality, there was about 14% in the quetiapine group versus 45% in the no quetiapine group. In terms of GCS, there was about a GCS of 11 versus 9 in the no quetiapine group. And both of these outcomes were found to be statistically significant. Similarly, for ICU length of stay and skilled nursing facility discharge, there was no difference between the two groups. Based off of these results, the authors concluded that patients who received quetiapine while in the ICU had improved neurological outcomes. Quetiapine use was also associated with lower rates of mortality. They also concluded that higher doses of quetiapine were associated with lower ICP and higher DPP, which led to a reduction in secondary brain injury. Now I wanted to talk about what I felt were the strengths and weaknesses of this study. Starting off, I thought that the study design accounted for potential confounders between the groups, the way that they decided to match patients based off of potential confounding variables, such as baseline characteristics and presenting ED vitals, as well as medications that were used to control ICP during their hospitalization. Furthermore, I thought the hypothesis tries to answer an unknown area in the literature. Previously, there was a lot of hesitation to use antipsychotics in traumatic brain injury patients, and this is based off of results in patients that received typical antipsychotics, such as haloperidol, and found to have both side effects as well as poor neurological outcomes. In terms of weaknesses, I thought that the retrospective design and the single-center nature of the study make the results a little less generalizable to a broader population. Additionally, the authors did not mention what dose is considered high-dose versus low-dose quetiapine, since the median dose in the study was about 50 milligrams and the mean number of doses was only 3. Furthermore, there was no assessment of other functional outcomes, such as Glasgow Outcome Scale. The endpoint of Discharge Glasgow Coma Score really only gives us a picture of the patient's neurological status at that time point, rather than their long-term functional outcomes. Additionally, I wish there was more detail into the skilled nursing facility discharges. So did the patient go to a subacute rehab versus needing 24-hour care at a long-term acute care hospital, or how many patients were discharged home? And lastly, they did not include any adverse drug reactions to the use of quetiapine. I did think that the motorality difference of 10% is both statistically and clinically significant, and based off of this, I calculated the number needed to treat in this patient population to be 9. However, the median discharge GCS difference of 12 versus 11 in the quetiapine group may not be as clinically significant because a GCS of 12 and 11 are both still considered moderate TBI. And to put into perspective the ICP lowering and CPP increase effects of quetiapine, I wanted to calculate based off of normal doses that we may see in the ICU, so 25 and 50 milligrams. So for example, 150 milligram dose may have an ICP decrease of about one millimeter per mercury and a CPP increase about one and a half millimeters of mercury, which may not be clinically significant when we have other agents to use for ICP lowering. The key takeaways for this study, quetiapine may reduce the risk of secondary injury caused by TBI-related agitation. However, the mechanism of quetiapine as a novel anti-inflammatory agent and its effect on functional outcomes are still being explored. Furthermore, I think that quetiapine could be a safe alternative to other traditional methods of TBI agitation control, such as benzodiazepines and the use of sedatives such as propofol. Further investigation with randomized controlled trials is warranted. Now for my first audience polling question, does your institution use quetiapine routinely for TBI agitation in the ICU? Okay, great. So about 60% of you said yes and about 40% of you said no. So about a 50-50 split there. I would say that this is still kind of emerging and especially at our institution it is really provider dependent, but I have seen growing use. And then for my next question, Would you start recommending the routine use of quetiapine for TBI patients based on the results of this study? Yeah, so overwhelmingly no. I fell in the same boat. I felt like I would not recommend the routine use of quetiapine. However, from this study, we know that it's not doing any harm by seeing that mortality difference. However, the neurological outcomes and the benefits there as a novel anti-inflammatory agent still needs to be explored further. Here are my references. And I want to thank you all for the opportunity to present. And what questions do you have for me? Thank you, Jessica. We'll open it up for audience questions now. Was there supplementary info about cause of mortality? It seems unlikely that agitation would be a cause of death. Would you be able to comment on that? Oh, yes. Thank you for the question. No, there was not any supplementary material in the study that broke down the cause of mortality. But yes, I agree. It is unlikely that agitation was truly the cause of mortality. It could have been a lot of different factors. Do you think quetiapine is neuroprotective? Or is agitation a good prognostic indicator? That's a good question. I am still unsure of the mechanism of quetiapine as being specifically neuroprotective. That mechanism is not completely understood. But I know that agitation in itself can increase intracranial pressure, which then can lead to poor neurological outcomes. So if we're controlling agitation, we may be able to prevent poor neurological outcomes. And I guess along those lines, could you comment on how quetiapine was chosen in these patients, or how it was used, and how it might influence the results of the study? I'm sorry. Could you repeat the question? Could you comment on how quetiapine was used in this study? Was there any indication that quetiapine was there any indication that sedation scores were used? Or any comments on the institution's use of quetiapine, and how this might have influenced the results? Yeah, so there was no indication in the study of how the institution specifically used quetiapine. In the baseline characteristics, they did mention other uses, such as benzodiazepines. And that was something that they ended up matching for. But there was no specific guidelines at that institution that they had mentioned in the study for the use of quetiapine, or what the indication was. OK, thank you. And that concludes our Q&A for this session. Thank you, Jessica. And now I'd like to introduce our second presenter, Suhaila Hamoud. Suhaila, can you please come up to the podium? Yes, thank you, Christine, for that introduction. Hello, everyone. My name is Suhaila Hamoud. And I'm the current PGY-2 Critical Care Pharmacy resident at St. Joseph Mercy Oakland in Pontiac, Michigan. And today, I will be presenting a recent publication within the Journal of Neurocritical Care. The respective study discusses the role of desmopressin in prescribed pre-injury antipayment medications. The objectives of this presentation will be to recall previous evidence regarding the use of desmopressin, which I will abbreviate as DDAVP throughout this presentation, for the management of hematoma expansion. We will analyze the outcomes of DDAVP use on hematoma expansion and mild traumatic brain injury. And last but not least, we will evaluate the place and therapy use of DDAVP in patients with mild TBI receiving antiplatelet medications. According to the Centers for Disease Control and Prevention, the last documented update in TBI events was 2014, which reported an average of 2.53 million ED visits, 288,000 hospitalizations, and 56,800 deaths during that year in the United States alone. The high prevalence of TBI-related events warrants evaluation of current management and to the future management of these injuries. Being implicated as a potential agent in the therapeutic management of hematoma expansion, DDAVP is a synthetic analog of arginine vasopressin, demonstrating selective V2 receptor agonist activity. It increases the endothelial release of large factor VIII von Willebrand factor maltumers and may also increase platelet membrane glycoprotein expression, thereby promoting platelet adhesion to the endothelium. Dosing ranges from 0.3 to 0.4 micrograms per kilogram, either administered intravenously or subcutaneously. The guidelines for the reversal of antithrombotics and intracranial hemorrhage recommend the consideration for a single dose of 0.4 micrograms per kilogram of IV DDAVP for ICH associated with aspirin or COX-1 inhibitors or adenosine diphosphate receptor inhibitors. In patients undergoing neurosurgery, platelet transfusion is suggested in conjunction with DDAVP administration as well. Previous studies have demonstrated a gap in the literature for the inclusion of patients with antiplatelet-associated bleeding events in TBI. Feldman and colleagues conducted a retrospective chart review of 124 patients with acute intracranial hemorrhage and known antiplatelet use. Patients were categorized into two groups of DDAVP or no DDAVP, and results expressed a reduction in ICH volume in patients who received DDAVP but found similar rates in thrombosis amongst both groups. Despite the reduction in ICH volume, the study did not account for confounding in those who also received platelet transfusions. Furey and colleagues conducted a much smaller study that included patients with TBI-induced ICH. Patients were randomized to receive DDAVP or a platelet transfusion, and overall they found similar rates of platelet inhibition and all-cause mortality between the two groups. In addition to the smaller sample size, another limitation exists due to the differences in disease severity that were present at baseline between both groups. Keeping this in mind, we can now take a closer look into the role of desmopressin on hematoma expansion in patients with mild TBI who are prescribed pre-injury antipilot medications. This was a retrospective cohort study of 200 patients with mild TBI and hematoma identified on CT who were receiving antipilot medications for various indications prior to their injuries. To note, the standard practice at the respective study institution included a CT on admission, six hours post, then every 24 hours thereafter. The objective of the study was to evaluate the effect of DDAVP on the incidence of hematoma expansion in patients with mild TBI receiving antipilot medications. The primary outcome was the incidence of hematoma expansion greater than 20% from baseline or a new hematoma on CT. Secondary outcomes include hematoma expansion greater than 33% from baseline, DDAVP-associated thrombosis, which was defined as a thrombotic complication occurring within 48 hours of DDAVP administration or admission if DDAVP was not administered, length of stay, Glasgow Coma score on discharge, as well as disposition. Patients met inclusion if they were at least 18 years of age or older, admitted to the level one trauma center of the respective study institution, had an evidence of a mild TBI on CT scan, and were prescribed pre-injury antipilot medications between July of 2012 and May of 2018. For patients included in the study, various baseline demographical data was collected and patients were categorized into one of two groups, those who received DDAVP versus those who did not. To confirm prescriptions for antipilot agents, a medication history was conducted or dispensing was verified with the respective pharmacy. Patients were excluded if their hospital length of stay was less than 24 hours, if they had no evidence of mild TBI on CT scan, or if they had DDAVP administered via an oral or subcutaneous route at a dose of less than 0.3 micrograms per kilogram. Dichotomous data was evaluated using Pearson's chi-squared or Fisher's exact test, whereas continuous data was evaluated using student's t-test for data that was normally distributed or a Mann-Whitney U-test for those that were not normally distributed. The univariate analysis that was conducted was conducted to assess differences at baseline between the two groups, so hematoma expansion was considered the dependent variable and associated factors were identified. Then a multivariate analysis was performed and risk factors for hematoma expansion were identified to account for confounding. It was built upon risk factors identified with a p-value of less than 0.1, coupled with clinical factors that would be expected to influence hematoma expansion, such as age, antipilot regimen, and anticoagulation. Variables with a p-value of less than 0.05 were considered independent factors for hematoma expansion. Results of baseline demographical data demonstrated an average age of 77 years for patients in both groups, and about 70% of patients experienced a fall in both groups as their primary mechanism of injury, which you can see in the table provided. Subdural hematoma and subarachnoid hemorrhage made up the majority of head injuries with no statistically significant differences in head injury classifications between the two groups. A subgroup analysis of GCS categories on admission revealed statistical significance among the groups with a greater percentage of patients in the DD-AVP group having a GCS of 13 to 15, which defines a mild TBI, and minimal alterations to their mentation. While the majority of patients received aspirin monotherapy, there was no statistical significant differences that were identified between groups for the types of antipilot agents that were used. There was, however, a statistically significant difference in the number of patients who received both DD-AVP and a pilot transfusion of about one to two units. A greater percentage of patients who did not receive DD-AVP received an oral anticoagulant, primarily Warfarin. However, there was no significant difference in the other reversal agents given besides DD-AVP. There was a statistically significant difference in the incidence of hematoma expansion, where almost two times the percentage of patients who experienced expansion greater than 20% from baseline or a new hematoma were in the non-DD-AVP group. Although the volume of expansion doubled from baseline, there was no difference between groups. For patients that did have expansion, a greater percent volume change was identified in the non-DD-AVP group. As mentioned in the previous slide, we saw a significant change in hematoma expansion greater than 20%, which was maintained even when a higher cutoff of greater than 33% was used. Thrombotic adverse events were further stratified by pathophysiology as arterial, such as an MI, or venous, such as a DVT or PE, with no significant difference between groups. DD-AVP did not impact length of stay or the level of consciousness depicted by the GCS at discharge. And last but not least, there was no difference in disposition at discharge as well. Here, in the univariate analysis, they analyzed the primary outcome to decipher what variables were associated with hematoma expansion. They found that the majority of patients who did not experience hematoma expansion were often younger in age, which was a statistically significant association between the two groups. An association between GCS on admission and hematoma expansion exists where more patients with a higher GCS on admission did not have hematoma expansion. There was a statistically significant association between higher doses of aspirin and the incidence of hematoma expansion with a P-value of 0.047. In this graph, I would like to direct your attention to the head injury classifications and the incidence of the primary outcome on the X-axis. Based on the documented P-values, we see that there was a statistically significant association between the two groups and the incidence of hematoma expansion and a statistically significant association between head injury classifications of subdural hematomas and multi-compartmental head injuries where a greater percentage of patients experienced hematoma expansion. Interventions performed to help mitigate hematoma expansion include DDAVP, prothrombin complex concentrate administration, platelet transfusions, and craniotomies. Administration of DDAVP was the only intervention with a statistically significant association with the incidence or lack of hematoma expansion where 81% of patients who received DDAVP did not have hematoma expansion. For the multivariate analysis, the base model reflects the variables that were statistically significant in the univariate analysis, such as age and DDAVP administration. And even though patients received platelet transfusions, we see that there was still an effect of DDAVP administration on hematoma expansion. Variables such as injury severity score, ADP receptor inhibitors, and PCC with a P value greater than 0.05 were omitted from the final model. In the final model, variables such as age, high-dose aspirin, multi-compartmental injury, and DDAVP remain statistically significant. DDAVP was found to be strongly associated with a decreased risk of hematoma expansion with DDAVP 75% less likely to cause hematoma expansion in a patient with mild TBI. Overall, the authors concluded that DDAVP was associated with a reduction in hematoma expansion in patients with mild TBI who were prescribed pre-injury anti-platelet medications. They deemed DDAVP as safe with the potential that it may be effective based on the results of this trial. And after evaluating the results of the subgroup analysis, they also concluded that the benefits of DDAVP on hematoma expansion and mild TBI was most notable in patients who were 86 years of age or younger, had a single head injury classification, and were prescribed low-dose aspirin of 81 milligrams. Some strengths of the study that I identified include pertinent inclusion and exclusion criteria for the outcome that was studied. Hematoma expansion is a common surrogate marker study that's often influenced by anti-platelet agents. A multivariate analysis was also performed to control for confounding variables such as platelet transfusions. A subgroup analysis of head injury GCS classifications was included to better assess disease severity. And as we noted, the majority of patients did have a GCS of 13 to 15. Daily CT scans were performed and read by two different specialists who were also blinded at the time, therefore minimizing bias that may be present. And the prescription for anti-platelet agents was verified via medication reconciliation. Some limitations include its retrospective study design and that it was conducted at a single center and primarily focused on patients with mild TBI. The use of DDAVP was not standardized by a protocol until October of 2014, which was two years after patient inclusion starting in 2012. Prior to 2014, it was prescribed based on provider discretion, which could have introduced variability in patient inclusion. A subgroup analysis of anti-platelet agents such as ADP receptor antagonists was not included. So it was difficult to assess whether more patients were on clopidogrel or ticagrelor in the study. And lastly, the time to DDAVP administration was not included in the final analysis. So we were not able to assess that this could have impacted the primary outcome of hematoma expansion. And in my search, I came across several neurocritical care trials same if you crash two, crash three with transexemic acid, but they actually found that time to medication administration had an effect on the primary outcome. So I felt that it may be beneficial to include this endpoint in future trials to assess the effect that it may have on hematoma expansion. Based on the identified strengths and weaknesses of the study moving forward, I believe more literature is necessary to reinforce the use of DDAVP for hematoma expansion in patients with mild TBI. A large prospective multi-center randomized placebo control trial may be beneficial to assess the efficacy of DDAVP in hematoma expansion. And for such a study, a patient-centered primary outcome rather than a surrogate marker of percent expansion will be more accurately able to assess the effects of DDAVP on the patient and functional outcomes moving forward. The study only included patients with mild TBI and while it can be generalizable to patients with this classification, generalizability is limited for moderate and severe TBI. Therefore, a study including more patients with all three classifications will create a study that is more externally valid. In the present study, patients who received DDAVP did so at a dose of 0.4 micrograms per kilogram. And some previous studies have documented administration of lower doses of about 0.3 micrograms per kilo. So a comparison of these two variations may allow better understanding of the dose-dependent effects of DDAVP. And last but not least, as I mentioned earlier, the specific ADP receptor antagonists were not identified. Therefore, a subgroup analysis of antiplatelet agents may demonstrate a more accurate assessment of their effects due to the variance in their reversibility. And now for our first polling question. What percentage of patients presenting with mild TBI on antiplatelet agents prior to admission received DDAVP at your institution? So, it looks like the majority of the audience answered that DDVP is not given for this indication, and it was kind of split between 1 to 25 percent. And I would say that seems pretty accurate, at least for how practice is at the institution that I currently practice at as a resident, where after speaking to some of my colleagues in the pharmacy department, patients presenting with mild TBI or even possibly other severities, we're going to evaluate benefit versus risk of if you've tried every possible option or intervention, is DDVP going to be an option initially, maybe further down the line? So I think it's interesting to see the split between the two different indications. For our second polling question, based on the current literature, would you recommend the use of DDVP in patients with mild TBI and receiving antiplatelet agents to prevent hematoma expansion? So, it looks like the majority of the audience answered no. And I think this could go both ways, and it might depend on the patient population that you see at your respective institution and the different intervention strategies or policies that you may have in place, but as healthcare providers, we often assess benefit versus risk of many recommendations, and I think it applies here as well, where decisions are patient-specific, where the benefits of using DDVP may outweigh the risk for one patient but not the other. So, I think it's just always important to consider the patients when making decisions. I'd like to thank everyone for your time, and at this time, I can take any questions that you may have for me. Thank you, Suhaila. We'll open it up to the audience for questions now. Can you further expand on your limitation that the primary outcome of hematoma expansion was not patient-centered and was a surrogate marker? Yes. So, in my literature search, I came across a few different studies that did look at hematoma expansion. So, as we know, percent hematoma expansion can be used to assess various TBI or hemorrhages in patients. However, for each patient, a percent of expansion or the volume of expansion may differ in terms of how it may affect the patient. So, for some patients, maybe a percent expansion of greater than 20% may have no effect on them, or depending on where the blood is able to move into the brain may also affect their ability and their functional status further down the line in the future. So, I think that when I state like a surrogate marker, I mean by a percentage is just a number. So, we don't treat numbers. We often use them to drive certain recommendations, but then also considering functional outcomes and overall how will this impact a patient's functional status, their life, and any other things that may be implicated, such as more patient-centered outcomes could be things such as mortality, so hospital mortality, ICU mortality, possibly mental status changes, and functional status, so things such as that. Do you think the study adequately assesses the safety of DD-AVP? I would say that the study did not consider any primary or secondary outcomes focused on the safety, so in terms of adverse effects. They primarily focused on the thrombosis that may be implicated in administering DD-AVP, which, as we know, is a potential adverse effect, usually more in patients who are at greater risk, so history of MI. So, I would say the study did not adequately discuss other adverse effects. The DD-AVP, as we know, can include things such as flushing, did patients have hyponatremia, so the incidence of hyponatremia among patients, as we know, is one adverse effect, one of the adverse effects, or peripheral edema. So, I would say that maybe moving forward, if they included some of these secondary outcomes pertaining specifically to the adverse effects, we would be able to better assess the safety, at least in this study. And can you comment on the use of platelet transfusions and how that may have influenced the results of the study? Yes, definitely. So, in the guidelines for the management of intracranial hemorrhage, they do recommend that if patients are undergoing a neurosurgical procedure, you can consider DD-AVP with a platelet transfusion. So, one of the key things is that in patients who are receiving DD-AVP, mechanistically, it's thought that you are improving the platelet function, and we don't necessarily know how patients reacted in terms of how well their platelet function was at baseline, since a test was not conducted for that. But from the standpoint of administering platelet transfusions, we're not sure if patients had less hematoma expansion because they were receiving platelets, so they were having less bleeding events, or was it the DD-AVP? So, when they conducted the multivariate analysis, they were able to adequately assess to see if this reduction in hematoma expansion was, in fact, due to the DD-AVP. Was it an influence of platelet transfusions? And they found that the platelet transfusions did not impact the hematoma expansion when DD-AVP was administered. So, I felt that that was controlled adequately to ensure that there was no confounding between those two variables. Okay. Thank you very much, Suhaila. That concludes our Q&A session for this journal, and now we'd like to introduce our final presenter, Lane Rehart. Good afternoon, everyone. My name is Lane Rehart. I'm a PGI 2 in critical care at Prisma Health Richland and the University of South Carolina. And to wrap up today's journal club, I'll be reviewing the RICH trial, which compared the effects of regional citrate and systemic heparin on dialysis filter lifespan and mortality in patients with acute kidney injury who required continuous renal replacement therapy. Continuous renal replacement therapy, or I'll refer to it as CRRT, is commonly used in our hemodynamically unstable patients with AKI. And in these patients, we also often use anticoagulation to prevent clotting of the filter and a decrease in membrane permeability, which ultimately maximizes our time of effective renal replacement therapy. We do have some guideline recommendations for anticoagulation in this population from KDGO in 2012. These guidelines recommend using anticoagulation in patients on CRRT if they don't have an increased risk of bleeding and if they do not already have a need for systemic anticoagulation. Additionally, the guidelines suggest using regional citrate over heparin if patients do not have any contraindications to citrate. The evidence for use of regional citrate came from several smaller trials. In 2016, a meta-analysis of 14 randomized controlled trials comparing regional citrate to heparin in critically ill patients requiring CRRT was published. Of the 14 studies included in this meta-analysis, 10 used systemic heparin. The meta-analysis found that overall, there were no differences in mortality between the regional citrate and heparin groups. However, the circuit lifespan was significantly longer in the regional citrate group with a mean increase of about 16 hours in that group. So, as I've mentioned, our options for anticoagulation in patients requiring CRRT are heparin and citrate. And when considering these two agents, we should consider several risks and benefits or pros and cons of each agent. Heparin can be given regionally or systemically. However, for this presentation, I'll focus only on systemic heparin since that was what was studied in the RITCH trial. So, because heparin is administered systemically, its use is associated with higher rates of bleeding complications. Additionally, there's always risk of heparin-induced thrombocytopenia when using this agent. Some benefits of using systemic heparin, though, are our experience with its use and monitoring as well as its low cost. Regional citrate, on the other hand, has been associated with a longer filter lifespan in previously conducted randomized controlled trials and has also been associated with a lower risk of bleeding complications since it's administered locally rather than systemically. The disadvantages of using regional citrate include its metabolic complications such as alkalosis and hypocalcemia. Additionally, regional citrate use requires stricter monitoring and protocols that institutions and providers may be less familiar with. Now that we've discussed the background, I did want to poll the audience now to see what everyone's current practice is for anticoagulation in these patients on CRRT. And the options are systemic heparin, regional citrate, and other. Okay, so it looks like about half of us are using regional citrate, and then the other half are using either systemic heparin or another option. So moving into the RITCH trial, we'll see if the results of that study support our current practices or suggest that we should be doing something differently. Okay, the objective of the study was to test whether regional citrate anticoagulation prolongs dialysis filter lifespan and decreases 90-day mortality in patients with AKI who required CRRT, and the investigator's hypothesis was that regional citrate would be superior to heparin for both of these endpoints. The RITCH trial was a randomized, multi-sender, parallel group clinical trial conducted from 2016 to 2018 in 26 ICUs in Germany, and the study included patients who were critically ill and had a clinical indication for CRRT or a severe AKI, as well as one of the following conditions, sepsis, vasopressor use, or refractory volume overload. Patients were 18 to 90 years old and were expected to receive ICU treatment for at least three days. Patients were excluded if they had an increased risk of bleeding, including active bleeding from GI ulcers, hypertension with an elevated diastolic blood pressure, intracranial hemorrhage or aneurysm, or neurosurgeries in which patients would be unable to receive systemic heparin, coagulopathies, thrombocytopenia, severe liver or severe pancreas disease. Patients with chronic kidney disease already requiring dialysis were excluded, as well as patients with specific causes of AKI, and patients with an indication for therapeutic anticoagulation, allergy to one of the study agents, a history of heparin-induced thrombocytopenia, and lactic acidosis with acute liver failure or shock were also excluded. The interventions studied in this trial were systemic heparin with a goal PTT of 45 to 60 seconds, compared to regional citrate, which was titrated to a post-filter ionized calcium of 0.25 to 0.35. And our co-primary endpoints were dialysis filter lifespan and 90-day all-cause mortality. Select secondary endpoints included ICU and hospital length of stay, duration and complications of CRRT, CRRT downtime, bleeding complications, and rates of infection. The investigators calculated a required sample size of 1,260 patients to provide 90% power to detect a difference in dialysis filter lifespan of 5 hours, and to provide 80% power to detect a difference in 90-day mortality of 8%, which was a change in mortality from 48% to 40% based on previously conducted trials. The investigators did plan for an interim analysis when a total of 400 patients were recruited, and this interim analysis would allow for proof of superiority of one of the agents, stopping for futility, and sample size recalculation with a maximum allowable sample size of 1,450 patients. So the study was stopped at the time of the interim analysis, so there were a total of 300 patients in the regional citrate group and 296 patients in the systemic heparin group. The mean age of patients was 68 years old, and approximately two-thirds of the patients were male. Over one-third of the patients in each group had CKD or an EGFR of less than 60 at baseline. Over 90% of patients in both groups were on vasopressors at randomization, and the most common indications for CRT were stage 3 AKI, decreased urine output or anuria, and fluid overload with edema. Looking at our primary endpoints, we'll start with dialysis filter lifespan. The mean filter lifespan was 44.9 hours in the regional citrate group and 33.3 hours in the systemic heparin group, with a difference of 11.2 hours between the two groups. The median values show a similar trend, and both are statistically significantly different. Figure A below is a Kaplan-Meier curve that also demonstrates that the regional citrate group had a significantly longer filter lifespan. On the y-axis, we have the probability of filter survival, and on the x-axis, we have the time from 0 to 72 hours. The probability of filter survival approached 0% in both groups at 72 hours because filters were required to be changed at this time based on manufacturer recommendations. So we do see that the curves start to diverge fairly early in this figure. Approximately 50% of the filters were still functioning in the heparin group at 24 hours, whereas in the citrate group, approximately 50% of the filters were still functioning all the way to 48 hours. The second of the co-primary endpoints in the study was 90-day mortality. Mortality rate was 51.2% in the citrate group and 53.6% in the heparin group, and neither the unadjusted or adjusted analyses showed a significant difference in mortality. Figure B is a Klaplermeyer curve depicting the overall probability of mortality from 0 to 90 days, and here we can see that there were no differences in mortality between the groups. Some of the notable secondary outcomes are shown on this slide. First, we see that total filter downtime was significantly lower in the regional citrate group. Next, if we jump down to the third line looking at bleeding complications, bleeding was defined as major bleeding requiring transfusion, bleeding requiring reoperation, and new onset of intracranial bleeding, and the bleeding rates were significantly higher in the systemic heparin group. However, red blood cell transfusion requirements on the line below we can see were similar between the two groups. The study also found a significantly higher incidence of new infections in the regional citrate group. There were no differences in other secondary endpoints of ICU or hospital length of stay or all-cause mortality at several different time points. For adverse effects, there were higher rates of alkalosis and hypophosphatemia in the citrate group as we would expect. There were lower rates of GI complications, which included any GI bleed requiring transfusion in the regional citrate group, and lastly, there were higher rates of hyperkalemia in the heparin group. In summary, the authors concluded that in patients with AKI requiring CRT, anticoagulation with regional citrate was associated with significantly longer dialysis filter lifespan compared to systemic heparin, and the trial was terminated early due to the apparent effectiveness of one agent for the dialysis filter lifespan outcome and for futility of the 90-day mortality outcome. Therefore, the trial was underpowered to reach conclusions about the effects of each anticoagulation strategy on 90-day mortality. Looking at some of the strengths and weaknesses of the study, its strengths include the fact that it was a randomized controlled trial and that it was the largest study conducted to date to my knowledge. Of the 14 trials included in the meta-analysis I discussed earlier, only one of those had just over 100 patients, and the rest were all less than 100 patients in both groups. Additionally, the results of this trial were consistent with previously conducted trials. For our limitations, one of the limitations of the study, I think, is that it was open label to the providers caring for the patients due to the complexity of titrating and monitoring both medications used in the study. As previously mentioned, the study did not show any differences between the groups in 90-day mortality, but it was underpowered to really make conclusions about that outcome. Next, a large number of patients were excluded from the trial throughout the course of recruitment. The majority of these were due to a history of dialysis-dependent chronic kidney disease and an increased risk of bleeding. And while it would not have been appropriate to include patients with increased risk of bleeding due to the use of systemic heparin in the trial, this is a patient population who might benefit from lower bleeding risk associated with regional titrate and who would be useful to study this agent in. Next, since one of the findings of this trial was a higher risk of bleeding associated with heparin, I think another limitation is that the bleeding complications or events were not well described. We know that rates of bleeding were higher in the heparin group and transfusion requirements were not different between the two groups, but the authors don't provide a breakdown of the bleeding complications, which would tell us if most of those differences in bleeding were driven by the need for reoperation or intracranial hemorrhage, which are two very different outcomes. Similarly, the trial also found increased rates of new infections in the regional titrate group, but did not provide any description on the types of infection, and I think our interpretation of this finding would also be different if most of the findings, most of the infections were bloodstream infections versus pneumonia. And lastly, I think an important addition to these findings of the study would be a cost-effectiveness analysis. In the beginning of the presentation, I mentioned that heparin is less expensive than citrate, but that only accounts for the actual drug costs. So, looking at the costs of CRT filters, costs associated with filter clotting, and therefore less effective renal replacement therapy, as well as costs associated with staff required to handle these complications, would be a useful addition to the study, as this has been reviewed on smaller scales previously, and in the data that I have pulled thus far have shown kind of mixed results as to which strategy is most cost-effective. With all that in mind, my conclusions and recommendations are listed on this slide. So, first, regional citrate was associated not only with a statistically significantly longer dialysis filter lifespan, but also a clinically significantly longer filter lifespan of 11 hours. For those that have moved to regional citrate anticoagulation with CRT, based on the previous data that has come out, this trial does confirm that this was an appropriate change to make. Regional citrate was also shown to be safer than systemic heparin with fewer bleeding complications, although the clinical significance of this finding is less clear, since we don't have information on the breakdown of bleeding complications. Next, if we are using regional citrate currently or would make a change to this based on the findings of the study, one role I think that we can play as pharmacists is in monitoring our patients. So, due to the metabolic complications of citrate, it's important that we monitor renal function panels, especially for the bicarb and phosphorus, as well as a serum ionized calcium every six hours. And lastly, future studies would still be required to detect any small differences in the effects of regional citrate versus systemic heparin on mortality, and to evaluate the new association between regional citrate and infection. And with that, I will conclude with our second polling question, just asking how the results of the RICH trial will impact your clinical practice. Okay, so it looks like about 40% of us would continue to use regional citrate, 13% would change to regional citrate, so that gives us about half of us would end today using regional citrate, and about a fifth of us would continue to use systemic heparin. That's very interesting. All right, and with that, I will conclude my presentation today and open it up to any questions. Great. Thank you, Lane. Let's see if we have any audience questions. What do you think is the reason for the higher infection and persistent AKI rates seen in the citrate group? That is an interesting question. I do not have a great reason for the new infection seen in the citrate group. I've talked about it with some of our pharmacists at my institution. They have also discussed this with our nephrologists and have not come up with a great reason that that would be the case, so I definitely think that would need further exploration. It appears that the reasons for filter changes wasn't protocolized in this study. Can you comment on reasons why they were changed in the different groups and if there was a difference? Sure. All filters were changed at that 72-hour time point, as recommended by the manufacturers. Other reasons for filter change, of course, included clotting, and this occurred in about 57% of the heparin group versus like 32% of the citrate group, so that was a significant difference. And then other reasons were not clearly defined, but examples they provided just included surgery, and that was higher rates of change for surgery occurred in the citrate group. Okay. I think that concludes our Q&A session. Thank you, Lane. All right. Thank you. Just making sure we don't have any final questions that came through for any of the presenters. If anyone has a last-minute question they can ask, but I think that concludes our session for today. Thank you to all of our presenters and the audience for attending. Please join us on the third Friday of the month from 2 to 3 p.m. Eastern Standard Time for the next Journal Club Spotlight on Pharmacy, and that concludes our presentation today. Thank you, everyone.

critical care medicine

neuroprotective effects

quetiapine

traumatic brain injury

improved outcomes

regional citrate

systemic heparin

dialysis filter lifespan

acute kidney injury