SCCM Resource Library-July Journal Club Webcast: Spotlight on Pharmacy (2022)

Video Transcription

Hello, 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 Melanie Perry, and I'm a clinical pharmacy specialist in trauma general surgery at Orlando Regional Medical Center. I will be moderating today's webcast.  A recording of this webcast will be available to registered attendees. You can log on to mysccm.org and navigate to the My Learning tab to access this recording.  Thank you for joining today. A few housekeeping items before we get started. There will be a Q&A section after each of today's speakers.  To submit questions throughout the presentation, type into the questions 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.  You may also follow and participate in live discussion on Twitter following hashtag sccmcppjc and hashtag PharmICU.  Please note the disclaimer stating that the content to follow is for educational purposes only. And now, I'd like to introduce your speakers for today.  Each will give a 15-minute presentation followed by a Q&A section. Our first presenter today is Dr. Heather Wilson, a PGY-2 critical care pharmacy resident at  Prisma Health Upstate in Greenville, South Carolina. She'll be presenting Evaluating Vitamin C in Septic Shock, a Randomized Controlled Trial of Vitamin C Monotherapy.  Our second presenter is Dr. Sam Markle, a PGY-2 critical care pharmacy resident at Sanford Medical Center in Fargo, North Dakota.  He will be presenting Comparison of Tenecteplase with Alzaplase for the Early Treatment of  Ischemic Stroke in the Melbourne Mobile Stroke Unit, a Phase II Randomized Open Label Trial.  And lastly, our third presenter is Dr. Aaron Ifoy, a PGY-1 pharmacy resident at the Medical University of South Carolina in Charleston.  He will be presenting on Antibiotic Timing and Progression in Septic Shock on Patients in the ED Presenting with Suspected Infection.  And now, I'll turn it over to our first presenter, Dr. Wilson.  Thank you so much for that introduction, Dr. Perry. Like mentioned, my name is Heather Wilson. I'm a current PGY-2 critical care resident in Greenville, South Carolina.  Today, for my journal club, I'll be presenting an article that was published in January of  2022 in Critical Care Medicine titled, Evaluating Vitamin C in Septic Shock, a Randomized Control Trial of Vitamin C Monotherapy.  Septic causes a severe inflammatory response in patients. There are a variety of different factors that contribute to this, including an increased  release of cytokines and an increase in release of reactive oxygen species. Vitamin C is thought to help mediate this process because it's antioxidant and also  has anti-inflammatory properties. However, the 2021 Surviving Substance Guidelines recommend against the use of IV vitamin C in adult patients with substance or septic shock.  The recommendation is a weak and a low quality of evidence recommendation. The literature regarding vitamin C therapy is mostly centered around a combination therapy  of hydrocortisone, vitamin C, and thiamine, or also known as HAT therapy.  Here are a few of the landmark trials that are evaluating vitamin C in septic shock. The first is titled Marek et al., which was published in 2017.  It was looking at patients with severe substance or septic shock who had HAT therapy versus control. This was the first study that showed an improved mortality in patients.  The second major study was published in 2019 by Fowler et al., or also known as the Citrus Olay Trial.  This patient population were patients who had sepsis with acute respiratory failure requiring mechanical ventilation.  With this, they were looking at vitamin C versus placebo. Of note for the Citrus Olay Study, they were doing 15 milligrams per kilogram every six hours.  This is substantially different from the first study, Marek et al., which looked at 1.5 grams every six hours.  To put that into a frame of reference, whenever we think about a patient in Citrus Olay, at  the 15 milligrams per kilogram, for an average 80 kg patient, that would be 4 grams, as opposed to the Marek et al. of 1.5 grams.  Citrus Olay, as one of their secondary outcomes, they did find a decrease in mortality in patients who utilized vitamin C.  The last study I wanted to highlight was published just last month in the New England Journal of Medicine, and it was looking at vitamin C monotherapy versus placebo.  They were also using the higher dosing strategy of the 15 milligrams per kilogram every six hours.  Their primary outcome was death of persistent organ dysfunction, and they actually found that vitamin C increased to this with statistically significant ratio of 1.21.  This brings us to the study today. This was the first study that was evaluating a continuous infusion of vitamin C for septic shock.  The objective of the study was to evaluate the effects of continuous vitamin C infusion on 28-day mortality in patients with septic shock.  They included patients within 24 hours of the onset of septic shock, which is pretty congruent with the current literature that's published.  The authors defined septic shock as known or suspected infection. Whenever they were evaluating this, they included patients that had a pro-cal greater than 2,  patients who had an order of antimicrobials, or if there was imaging or team impression that the patient was likely to have an infection.  Patients also had to have an evidence of a substance response. This was defined as a service criteria of 2 out of 4 or a change in their service score greater than or equal to 2.  Lastly, patients that were included also had to have evidence of shock.  The authors defined this as a need for vasopressors to maintain a MAP greater than 6 after patients had gotten the appropriate 30 milligrams per kilogram of fluids.  Patients were excluded for reasons you can see on the right.  The study was a randomized placebo-controlled study that was conducted at five different sites.  Out of those sites, four of them were community centers with one being an academic medical center.  The authors gave a vitamin C 1,000 milligram bolus and then followed it by continuous infusion of 250 milligrams per hour.  The authors did this because they thought by having a consistent delivery of vitamin C, they could get more equal vitamin C plasma levels.  This dosing strategy was picked based off the Merck et al study, which was 1.5 grams every six hours, so they just divided it to get the same amount per hour.  Interventions were continued for 96 hours, or if the patient remained vasopressor-free for two hours. All other treatments for septic shock were at the team's discretion.  Their primary outcome was all-cause 28-day mortality.  Secondary outcomes included all-cause ICU mortality, time to lactate clearance, need for renal replacement therapy, and also durations of hospital stay.  The study wasn't an intention to treat analysis.  The study was intended to provide an overview of the study.  The study wasn't an intention to treat analysis.  They had calculated that they need 124 subjects to detect a 20% decrease in absolute mortality  with an 80% power.  The authors estimated a 20% decrease based off previous literature.  Merck et al found a 30% decrease in mortality, and Citrus all they found around a 16% decrease in mortality.  The statistical tests were appropriate for the study.  The statistical tests were appropriate for the indication.  They had 271 patients who met inclusion.  Out of this, they only had 124 that were included in analysis.  The main exclusion criteria that patients met were that they weren't identified within 24 hours of their septic shock.  The second most common exclusion criteria was a history of kidney stones.  Here are the baseline characteristics of the patients that were included.  Although none of them were statistically significant, I think there are some that could be clinically relevant.  The first would be our SOFA score.  Whenever we look at the patients, the average SOFA score was around 10, indicating that these were relatively high acuity patients.  The second is the need for renal replacement therapy.  So this was at enrollment before the patients had received any study drug. We also excluded patients who had a history of end-stage renal disease needing dialysis.  When you look at these percentages, there was 10% in the vitamin C versus 1.7% in the placebo.  So again, although not statistically significant, it's something to keep in mind when you interpret the results of the study.  Also looking at time from pressure initiation to study drug, it was around 11 hours.  Again, this is very similar with the current literature that's published for vitamin C and septic shock.  Patients who had their antibiotics start within an hour was actually pretty low in the study. It was only around 50%.  This is, again, important to think about whenever we're seeing the adherence to the sepsis bundle that is recommended through the 2021 guidelines.  And lastly, although the study was looking at vitamin C monotherapy, almost half of the patients also received adjunct hydrocortisone.  So again, this is something to keep in mind when you interpret the results of the study.  In regards to the primary outcome of 28-day mortality, vitamin C did not demonstrate any benefits.  There were some benefits in the secondary outcomes.  At first, we're looking at renal replacement needed during the 96-hour study window.  When interpreting these results, this is, again, important to think about that 10% of our patients in the vitamin C group already needed some type of renal replacement therapy  prior to vitamin C being prescribed. So this was statistically significant.  Remember keeping in our baseline characteristics.  The other statistically significant finding they found in their secondary outcomes was the total fluid that ministered during the six hours after drug initiation.  The authors also conducted a subgroup analysis to determine if there was any patient population that did see a benefit with vitamin C therapy.  They first evaluated the patient population for vitamin C. They also conducted a subgroup analysis to determine if there was any patient population  that did see a benefit with vitamin C therapy.  They first evaluated steroids and did not find any difference.  Second, they evaluated SOFA score.  They wanted to see if patients that possibly had a lower or higher acuity would they possibly  benefit from vitamin C, and they did not find anything that was statistically significant.  They did also want to look at ventilation status, and this was based off the citrus olive study.  So remember those patients were mechanically ventilated, so the authors were curious to see if that finding would translate into their results.  They did find a decrease in mortality with vitamin C therapy in patients who had positive pressure ventilation, which included both non-invasive and invasive mechanical ventilation.  They also looked at hypoxic respiratory failure, defined as a PAFO2 less than 300, and they did not find it to be statistically significant.  The authors concluded that vitamin C monotherapy did not reduce mortality in septic shock patients.  They also found no benefits regarding their secondary outcomes, including ICU mortality, improvement in SOFA score, and time to shock resolution.  Overall, the findings did not support the use of vitamin C monotherapy for septic shock.  Whenever I evaluate this literature, I think there are some strengths of the study.  The first being a high patient acuity, but they again did not find any difference in a high patient acuity, but they again having a SOFA score around 10, and 50% of the patients  were requiring some type of positive pressure ventilation.  I think a second strength of the study was that it was evaluating vitamin C monotherapy, which is a current gap in current literature.  However, there are several notable limitations of the study, the first being the differences in the baseline characteristics.  The most notable one would be the difference between the renal replacement therapy.  I think this is clinically relevant because whenever we evaluate the plasma and vitamin C levels, renal replacement therapy can decrease up to 50% of that.  This would mean that those 16% of patients who needed renal replacement therapy, over 50% or about 50% of their vitamin C was being removed through the renal replacement therapy.  Another limitation of this study is the varied utilization of concomitant therapies, in particular the hydrocortisone.  I think this is a limitation because whenever we think about steroids, they have been shown to decrease our time to shock resolution.  Knowing that, it could have impacted our secondary outcome.  Another limitation is the vitamin C dosing.  This was the first study to look at a continuous vitamin C infusion.  I know this is a limitation because it makes it very hard to interpret the current literature when there's so many different dosing strategies.  However, it could also be thought of to be a strength because of the fact that they were trying something new to see if it potentially did have benefits.  The last limitation I identified in the study was the fact that they were missing our standard of care.  It's important to think about that only 50% of the patients received antibiotics within one hour, which could have impacted a lot of their findings.  The overall clinical application, there was no identified benefits in the primary or secondary outcomes in this study.  On the flip side, though, there were no serious safety events reported.  I think there's a limited evidence of benefit of vitamin C therapy.  Whenever we think about the study that was just published in 2022, it's important to think about the study that was just published in 2022, their number needed to harm was around  16.  When we kind of think about our other studies, so for example, our citrus olive study, which showed a decrease in mortality, their number needed to treat was six.  So it's hard as a clinician to take away the benefits versus the risks whenever we think about there is conflicting evidence that's currently published.  Another thing to think about is that there is a variation in dosing strategies used for septic shock.  So like I mentioned, there's one that's a weight-based, the 50 milligrams per kilogram, one that's not weight-based of 1.5 grams every six hours, and then also now a continuous  infusion.  I think an area that could potentially be evaluated is our mechanically ventilated patients because we did see that our positive pressure ventilation patients did have a benefit in  the subgroup analysis, which would kind of be congruent with the citrus olive study that was published.  Lastly, it's also important to think about that vitamin C treatment therapy can be expensive.  Here at Prism Health, an estimated cost for a patient to have the same treatment as what was studied in this trial would be around $1,500.  Overall, I would not recommend vitamin C monotherapy for septic shock.  To take away points from this presentation, I hope that you remember that there is conflicting literature regarding the utilization of vitamin C for septic shock.  There's also a variety of dosing strategies, so make sure that you're aware of that if you are recommending it.  And lastly, I believe that this literature supports the 2021 Surviving Substance Guidelines.  Here's our first polling question. Does your institution currently utilize vitamin C for septic shock?  As you can see here, the vast majority is no, and that's the same here at Prisma Health Upstate. We do not utilize vitamin C for septic shock.  Now moving on to our next polling question. What do you believe is the biggest unanswered question regarding vitamin C therapy for septic shock? Do you think it's time,  as far as time to initiation of vitamin C? Do you think it's combination therapy? I've seen what would be monotherapy versus combination of HAP therapy.  Or do you think it's also lastly dose? So do you think that's also evaluating which dose do we believe to have the greatest benefit?  So I think the majority here would be combination therapy. I think all three of these are answer questions regarding vitamin C. I think I'm also most interested in time, personally.  There is a study going under looking at the initiation of vitamin C in the ED within six hours. I think that would be an interesting study  to see if maybe that would change the results that we see in the literature.  And now I'll open the floor for any questions.  Dr. Wilson, our first question is, did they break down the source of infection in the study?  Yes, they did break it down based off the source of infection in the study. And I believe the most common was a pulmonary, or excuse me, it was a urinary.  Our second question is, other than the potential PK benefits from the continuous infusion of vitamin C, why do you think they chose that particular dose or duration?  I believe they chose the duration of 96 hours because that's what currently has been studied and that's what it originally showed mortality benefit. And that's also why I believe  they picked the 1.5 grams every six hours. So that's from the Merica All study. So they took that dose and they extrapolated  to what would be an equivalent dose in a continuous infusion.  And lastly, if you were to conduct this study, is there anything that you would change  about the design or the outcomes?  I don't think I would change anything about the outcomes. I think some things I would change in the design, I think would probably be the time. Like I mentioned,  I think that's the biggest unanswered question. So they were looking at continuous infusion, which potentially would have seen a benefit maybe,  but I think if they would have initiated earlier, then we maybe would have seen a benefit kind of based off the literature of the Orange's trial,  which showed that less than 12 hours initiation, they did have a decrease in their time to shock resolution.  Thank you for your response. That concludes our Q&A session. Thank you, Dr. Wilson.  Before moving on to our next presenter, we would like to ask a brief polling question regarding today's attendance to gain a better understanding of our overall attendance  to ensure continued supportive spotlight on pharmacy webcasts. How many attendees are viewing this webinar with you?  Just me, two to five people, five to 10 people or greater than 10.  Thank you for participating in the poll. Now I'd like to introduce our second speaker, Dr. Sam Markle.  All right, thank you for that introduction here today, Dr. Perry. As mentioned, my name is Sam Markle, a current PGY2 critical care pharmacy resident at the  Sanford Medical Center in Fargo. Today I wanted to present on the TASTE-A study, which is a comparison of tenecteplase  and alteplase for early treatment of ischemic stroke in the Melbourne mobile stroke unit.  Before we dive into the trial proper, I wanted to set the stage with a little bit of a background discussion on our topic today.  And so as we know from our most recent stroke guideline update, thrombolytic therapy with alteplase still remains our standard of care for the treatment of those patients that have  a disabling acute ischemic stroke. And a lot of our evidence supports that the time to thrombolytic therapy administration  is a real strong driver for positive outcomes in these patients, leading to the common phrase, time is brain.  And while alteplase has traditionally become our standard of care owing to the early studies  for its approval, there has been a resurgence in interest in the utilization of tenecteplase  as an alternative thrombolytic agent, mainly owing to its practical advantages over alteplase and its potential to overall decrease our door-to-needle times.  However, there is limited evidence to support its utilization in ischemic stroke, which is where most of the more recent studies come from.  When we compare these agents together, tenecteplase has the benefit of a longer free plasma half-life  that ultimately reduces its need for a prolonged infusion and allows for a single one-time  bolus dose, has enhanced fibrin specificity that's theorized to improve its overall clinical  efficacy and reduce the potential for hemorrhage, as we've seen with some of our myocardial  infarction studies, and also has a much easier preparation and administration scheme, allowing  for simple, fast preparation either at bedside, CT scanning, or even in the field, as we'll see with today's study.  And this more rapid administration avoids that prolonged one-hour infusion of alteplase that ties up an IV line and can potentially complicate transfers, as well as oftentimes  gets missed during a complicated and busy ED resuscitation. So when we compare the overall body of evidence to support tenecteplase over alteplase, it's  really an overall muddy picture currently. We have five major clinical efficacy studies that have been published thus far, and that's  on top of many of the dose-finding trials that existed previously. And these studies had a very heterogeneous population and utilized varying study designs  that ultimately limit our ability to make a strong consensus statement on what the evidence speaks to.  I will note that there are currently five ongoing trials that are a larger phase three  studies that will hopefully provide a little bit more information as to exactly where tenecteplase  falls in our clinical spectrum, and maybe identify patient populations who would benefit the most.  But when we take all of these studies into account currently, there have been two studies that have a signal for superiority, these being the TACE trial and the Xtend IATNK.  However, these trials only included patients with large vessel occlusion and had a very strict occlusion criteria that limits its overall generalizability.  The largest of the studies published currently is the phase three NORTES trial, which published in 2017, had over 1,000 patients, but ultimately was a neutral trial.  It did not demonstrate superiority between the two groups, but ultimately didn't lead to an overall increase in harm in the general patient population.  This trial, though, was limited by enrolling mostly minor ischemic strokes with a median NIH of around five, and using a higher than typical dosing regimen at 0.4 milligrams per  kilogram rather than the 0.25 that we typically would see evidence speak to. As a result of this, the authors conducted a follow-up study, the NORTES2 trial, which  was specifically enrolled patients with a median NIH of six or greater in order to account for that limitation.  And in the first cohort of this study, which used the higher dosing scheme, ultimately had to be stopped early due to an increased signal for mortality in the patients that  received that higher dose of tenecteplase. And so really, we kind of currently stand in a crossroads where we have good evidence  to say the 0.4 milligram per kilogram dose is inadequate, but we still don't necessarily know where the 0.25 dosing scheme falls in our clinical spectrum.  And so this is where we come to more recent trials, such as the TASTE-A study, which set out to compare these two agents for the treatment of acute ischemic stroke in a pre-hospital  setting via a unique mobile stroke unit design. This was a randomized open-label Phase II clinical trial conducted at a mobile stroke  unit supplying five different hospitals in Melbourne, Australia. And these patients who would be included in the study were assessed in the field using  the NIH scoring and also received in-field brain imaging through an onboard CT scanner in the mobile stroke unit.  Eligible patients were randomized one-to-one to either receive tenecteplase or alteplase at the doses listed above, and then would be transferred to a receiving hospital where  a repeat CT scan was performed immediately in order to assess the primary outcome and determine further therapeutic intervention.  The study population was very similar to what we've seen with previous stroke studies enrolling  patients within four and a half hours of onset, and they had to have some degree of baseline independent mobility or a functional status less than or equal to three on the modified  Rankin scale, which would indicate potential benefit from therapy. They did exclude patients who had the standard TPA exclusions, anyone with rapidly improving  symptoms, and those with a large hypodense lesion detected greater than a third of the MCA territory or equivalent on a non-con CT scan.  Their primary outcome for the study was the volume of the perfusion lesion that was assessed on imaging arrival to the hospital, mainly looking at an imaging-focused outcome.  Their secondary outcomes were quite numerous, looking at both clinical and imaging efficacy endpoints as well as procedural and safety outcomes.  I simply included some of the more common patient-centered outcomes that we might care about when we're focused on patient care.  The statistical analysis design was ultimately decided on a 104-patient sample size, which would give the authors 90% power to detect a 13-mil difference in the post-treatment  lesion volume. And this was based on pre-published data from the TASTE trial and some author inferences as to differences in the overall study design.  It was analyzed as intent-to-treat and used a unique zero-inflated negative binomial regression  model to account for the fact that there may be imbalances in the number of zero-volume lesions that were detected when they assessed the primary outcome.  Ultimately, 530 patients were screened for inclusion in the trial, and after excluding about 400 or so of those patients, we ended at our 104-patient sample.  The median age of this population was 73 years. Their baseline NIH was around 8, which is slightly lower than what we've seen in most of our stroke literature.  46% of these patients had a large vessel occlusion, and there was a higher rate of prior stroke detected in the alteplase group, which could bias our overall outcomes.  For the primary outcome, tenecteplase did result in a lower perfusion lesion volume present on hospital arrival, a difference of 23 milliliters that met statistical significance.  When we look at our secondary outcomes, we only had one major outcome meet statistical significance, and this was the reduction in the NIH stroke scale between mobile stroke  unit and hospital arrival, though the clinical relevance of this finding is questionable, as the difference was only one point on the 42-point NIH scale.  When we look at any of our longer-term outcomes or functional outcomes, we show no difference between the two groups, which could potentially be due to underpowering.  Within our procedural outcomes, however, tenecteplase was associated with more rapid administration  of thrombolysis, both from CT scanning and from the arrival of the mobile stroke unit at a difference of about seven minutes that accounts for the more rapid preparation and  administration of that medication. So the authors, as a result of these findings, concluded that ultra-early administration  of tenecteplase reduced the volume of post-treatment perfusion lesion, led to a greater ultra-early  clinical recovery, and was initiated faster than alteplase at a mobile stroke unit. But I think it's important to, of course, critique these findings as we apply them to  our patients in clinical practice. So first, let's talk about the strengths. This was a randomized controlled trial with a very pragmatic design and looked at a unique  pre-hospital population in a mobile stroke unit design that's not typically seen in most modern U.S. practices.  It utilized the most evidence-based dosing available for tenecteplase rather than the 0.4 milligram per kilogram dose that showed worse outcomes.  And though this was an open-label study, they did blind the outcome assessors to allocation to help to potentially reduce the bias that that would introduce.  The study does have a decent amount of applicability to rural healthcare centers and centers that  require to transfer patients with stroke, as resource-scarce areas might benefit more from the practical advantages of tenecteplase than other institutions.  However, I do think that the limitations of this study outweigh many of the pros. The study obviously has some major applicability concerns, particularly in our more modern  hospital-based practice, as this did look at patients who were treated a median of 95 minutes from stroke onset, which is considerably faster than what we will typically see in  most of our hospital-based practices. It looked at a non-clinical primary outcome focused on an imaging assessment, which while  it may show some differences between the two medications, it's ultimately not a patient-centered  outcome that we care about when directing therapy towards patients, and ultimately the trial was underpowered to detect differences in those longer-term outcomes.  There was an unknown pretreatment perfusion lesion volume between the two groups, which means any differences could be due to baseline differences between the groups.  There was no intracranial hemorrhage reported in either group in the study, which could limit and potentially show a bias in our overall safety event reporting.  And last but not least, and potentially worst, the timing of the imaging for the primary outcome assessment might bias the overall findings in favor of tenecteplase.  The imaging assessment was conducted at a median of 47 minutes after therapy was initiated,  which means that while tenecteplase had finished, the alteplase infusion would not even have  completed as of this time, meaning that any overall outcome differences might be automatically  favoring tenecteplase, and this is also backed up by the fact that we showed no differences in some of our longer-term outcomes between the two groups.  So in my personal opinion, I somewhat agree with the author's conclusion in that tenecteplase  was associated with a faster time to thrombolysis and could potentially reduce our perfusion lesion volumes.  I ultimately feel that the trial limitations prevent really strong direct application of these results to my own clinical practice.  With that said, however, I think the findings do build upon the existing literature base in support of tenecteplase, mainly due to the limited signals for harm, both in this  study and in previous literature, and the practical advantages that exist. I think that tenecteplase can be considered as a reasonable alternative to alteplase,  pending the results of some of the larger phase III clinical studies that will hopefully provide additional support.  So with all that said, this brings me to my first audience polling question today. Which thrombolytic agents does your institution have available for the treatment of acute  ischemic stroke?  Okay, that's actually a fairly interesting spread of results. It's interesting to see that some institutions have already made some switches over to connect  to place, especially given that some of the studies have yet to publish a lot of their data, but it's nice to see kind of the spread of implementations, and it'd be interesting  to repeat this question after those larger clinical trials have been published. So we'll move on to our second audience polling question here, which is, based on the current  literature, do you believe there's sufficient evidence to recommend connect to place as an alternative to alteplase for ischemic stroke?  Okay, that's actually fairly consistent with what I expected to see as the results, with the majority of people saying that, yes, I think there's sufficient evidence, but I would  like to see a little bit more study, which I think those larger clinical trials that should be publishing within the next few years will help to provide additional evidence in  those specific areas. Okay, so with all that said, I wanted to open things up for questions, and thank you all for coming to the presentation.  All right, Dr. Marko, our first question is, since most studies looked at MRS score at 90 days as a primary outcome, when looking at figure three, do you think there's clinical  relevance to the greater percentage of MRS scores, zero to two, for tenecteplase? I think that's a really great point, and I think this trial ultimately was underpowered  to really show major differences in those outcomes. I think if we were to have a larger population and extrapolate things into an overall meta  analysis when some of these other studies come out, I think those trends might be a little bit more significant, but I do think that those patients that have that good functional  outcome that we would normally assess have been slightly favoring tenecteplase in most of the studies, and so I think it's reasonable to at least kind of push for more study in  that area. All right, our next question is, did the authors remark on occlusion location, or they also any mention of large vessels?  So in the trial, there was a 46 percent of the overall patient population did have a large vessel occlusion.  I would have to double check exactly if they specified on the specific locations, but in my first perusal of the trial, I don't believe they specified whether they were specifically  looking at, like, M1 versus ACA or PCA occlusions, but excellent question. Okay. Thank you. Do you think there's a larger number of patients in the T and K group that had LVOs?  Not sure of the abbreviation, but it looks like LVOs. So based on the baseline characteristics, it seemed that the number of large vessel  occlusions overall were well balanced between the two groups, but that definitely would be an area that further study could kind of elucidate differences, particularly looking  at the EXTEND-IAT and K trial, which specifically looked at more of those large vessel occlusions  who would be thrombectomy capable, which may kind of indicate that tenecteplase may be more effective in those specific patients. But overall, the groups were fairly well balanced.  And then it looks like we have two more questions if we have time. Absolutely. How does the number of patients included in the clinical trials comparing alteplase to  tenecteplase compare to the number of patients in the trials that originally got alteplase approved for stroke? That is a fantastic question.  The overall evidence base for alteplase is still kind of a relatively shaky area in overall  practice and really coming down to just the NINDS trial and the ECAS-3, which demonstrated potential outcomes and had relatively lower patient populations compared to especially  the NORTES trial. And as more of these other trials for tenecteplase versus alteplase come out, it does kind of  draw into question whether or not, you know, we're comparing tenecteplase to alteplase, but is alteplase truly the end-all be-all for stroke management?  And so I think it would definitely be an area of continual discussion and a gray area in terms of which patients we're selecting for overall stroke management.  Okay, and our final question is, are there any patient populations you would not recommend tenecteplase in for the 0.25 mg per kg dose?  That's another really great question. As of right now, it's a little bit more difficult, in my personal opinion, to say if there are  specific populations that wouldn't necessarily benefit. A lot of it comes down to the specific inclusion and exclusion criteria in the studies, and  so I think that would kind of be my biggest area. But until we have the results of some of the larger trials that kind of give us a more  specific patient population, I don't think I can make a really strong statement on which patients I would say should get it or shouldn't get it. But excellent question.  Dr. Marko, thank you for your responses. That concludes our Q&A session. And now we'll have our final speaker, Dr. Aaron Ifoy. Thank you, Dr. Perry. Thank you, Dr. Perry.  So as she said, my name is Aaron Ifoy. I'm a PGY-2 critical care resident here at the Medical University of South Carolina,  and today I'll be presenting my journal club on a manuscript that was published in January 2022 this year in the Chess Journal by Roshan Basira and colleagues entitled Antibiotic  Timing and Progression of Septic Shock Among Patients in the ED with Suspected Infection. So as many of us know, sepsis and septic shock occur fairly common in the intensive care  unit and the emergency department and is associated with high morbidity and mortality, reaching as high as up to 40% in some cases.  The current practice, as outlined by the Surviving Sepsis Campaign from 2021, is to treat patients with antibiotics within one hour of presentation.  Now here recently, there has been some discussion to remove patients with sepsis in the absence  of shock from the CMS SEP1 core measures, and this has been based on previous literature that has been retrospective in nature and also not distinguishing patient severity of  illness as a marker for the risk of progression to septic shock. So this shines light on a gap in literature of whether the severity of illness of patients  suspected to be septic or in septic shock actually impacts the outcomes that are associated with the timing of antibiotics.  So the objective of this study was to determine if time from ED presentation to administration  of antibiotics leads to progression of septic shock among patients with suspected infection. So now moving on to the methods of the study, this was a retrospective cohort study that  was looking at adults with suspected infection and first antibiotic administered within 24 hours of triage.  So the authors actually define suspected infection as a patient having blood or body fluid cultures obtained and antibiotics started within four hours of one another.  The inclusion criteria were patients that were 18 years or older who sought treatment in the ED from March 2007 to March 2020.  Patients were then excluded if there were no reasonable ED discharge time or no time documented of first antibiotic administration as they would be unable to determine how long  the delay would occur. And the patients were also excluded if they presented in septic shock, which they went  on to define as vasopressor infusion started within three hours of ED triage time, excluding  boluses, or if they received initial antibiotics more than 24 hours after hospital administration or admission.  So the study went on to look at four different outcomes, those being hospital length of stay,  time to initial antibiotic administration, rate of progression of septic shock, and lastly end hospital mortality.  So for the statistical analysis that they conducted, they used Manu-Whitney test and Chi-square test to compare the patients who progressed to septic shock and those that did not.  And they also conducted a univariate logistic regression to determine variables that were associated with antibiotic administration delays within the first, third, and fifth hours.  They then also conducted a second univariate logistic regression that was used to determine  variables that were associated with progression of septic shock for in-hospital mortality. And they did this based on using both the sepsis 2 and sepsis 3 diagnostic criteria.  And I will get into why they used both of those in the study in a few slides. Lastly, they calculated a propensity score that was used to stratify patients based on  their severity of illness. And to do this, they used both QSOFA scores and SIRS scores. So when looking at the actual design of the study, roughly 78,000 patients were screened  for inclusion for this study, of which 74,114 patients actually met inclusion criteria and underwent the final analysis.  Of those 74,000 patients, a total of 5,510 patients ended up progressing into septic shock, with the remaining 68,604 patients not progressing to septic shock.  So before getting to the results, I'd like to talk a little bit about the baseline characteristics.  Here on this chart, there are just a few of the ones that they included in the study. And as you can see in the right column, all of them were actually found to be statistically  significant. However, there are a few that I would like to point out that I thought were clinically significant as well.  The first being the age of patients that were included in the study. So for patients that ended up progressing to septic shock when using the sepsis 2 definition,  they were actually found to be roughly seven years older than the patients that did not progress to septic shock.  Now looking at the SOFA score, the patients that ended up progressing to septic shock also had a SOFA score that was roughly two times higher than those that did not progress  to septic shock. Assuming that those patients would be more acutely ill. But when you look at how many patients ended up scoring a QSOFA score greater than or equal  to two, or a SURF score that was greater than or equal to two, you can see that more patients  that did not progress to septic shock had that score greater than or equal to two compared to those that did.  So suggesting that more patients could have been diagnosed with septic shock, however, they did not have a much higher acuity of illness at the time of ED triage.  So moving on to the actual results, I'll start by discussing these three line graphs that were included in the study.  Each of them depicts the percentage of patients that progressed to septic shock, depending on how long antibiotics were delayed.  However, each of them does look at a different subset group of patients, and I'll talk about each one separately.  So starting with the first one, this is looking at all the patients that were included in the study, so the 74,400, and looking at at what rate did they progress to septic shock  depending on how long antibiotics were delayed. And as you can see, the rate of progression to septic shock was actually at its highest  within the first five hours of antibiotic delay, and then after that five-hour marker, the rate of progression to septic shock tends to plateau.  So keeping that in mind, we'll move on to this second graph, and this is where the study actually shines in the highlight of the point that they wanted to come across.  So this study, again, or this graph is looking at the percentage of patients that progressed to septic shock.  However, this is where they split up the patient's severity of illness into three different groups,  the bottom line being the patients that were the least severely ill, in the middle, patients  that were moderately severely ill, and then the top line being the most severely ill patients. As you can see, regardless of severity of illness, the highest risk of progression to  septic shock still occurred within the first five hours of antibiotic delay. However, you can note that the incline in progression was at its highest in the patients  that were the most severely ill. So as patients were presenting more acutely ill, they did have a much higher risk of progressing  to septic shock compared to patients that were not as acutely ill. Finally, I'll move on to the third line graph that I was discussing.  This actually looks at only the patients that ended up progressing to septic shock. So this is the 5,510 patients that progressed.  And looking at this, you can see, again, still within the first five hours of antibiotic delay, the rate of progressing to septic shock is still at its highest at this point.  As you can see, this has been a consistent trend amongst all three graphs, depicting how important it is to start antibiotics as soon as possible, as the rate does increase  as each hour passes by. So now I'll talk a little bit about this table that was included in the study as well.  And the highlight of this table is looking at why the sepsis-2 and sepsis-3 definitions were used to determine septic shock in the patients in the study.  The reason they wanted to use both is because they wanted to be able to include as many patients as possible.  So patients that often are using the sepsis-2 definition to define septic shock only required  to have refractory hypotension, whereas using the sepsis-3 definition to define septic shock,  patients have to be hypotensive, have an elevated lactate, and also require vasopressors.  So again, most of the results that are presented here on this slide are, again, statistically significant.  However, there are some, again, that I would like to point out that I find to be clinically significant.  So as you can see, starting at the top of the chart, you look at the two scoring systems that were used for the propensity score that was used to determine the severity of illness  for these patients. The odds ratio for the SOFA score was the highest amongst the two and much higher than  that of the SIRS score, suggesting that patients with a SOFA score that could be a better predictor  for patients regressing the septic shock with an odds ratio of 1.45 using the sepsis-2 definition and an odds ratio of 1.40 using the sepsis-3 definition.  Now, that's not to say that the SIRS score was not a good predictor, as its odds ratio as well was above 1 with 1.9 in the sepsis-2 definition and 1.20 in the sepsis-3 definition.  So both of these being statistically significant, showing that they are good predictors for determining if patients have an increased risk of progressing to septic shock.  The next point that I would like to look at is the actual source of infection that they used in this study.  So patients that presented with a skin and soft tissue infection actually had the highest risk of progressing into septic shock with an odds ratio of 1.42 in both the sepsis-2  and sepsis-3 definitions. Another thing to point out here is actually looking at the urinary tract infections.  So with urinary tract infections, there was actually a decrease in the risk of progression to septic shock with an odds ratio of 0.91 using the sepsis-3 definition, as this was  the only definition that the odds ratio was found to be statistically significant. So having to look at the patients that have an elevated lactate as well as hypotension  and vasopressor use, if they're presenting with a urinary tract infection, there is a good chance that they do not have a high risk of developing into septic shock.  So this brings us to the author's conclusions for the study, and they were able to find that with each passing hour in the ED, risk of progression to septic shock increased by  4% while adjusting for severity of illness. This is important to note if you consider the new recommendation from the 2021 Surviving  Sepsis Campaign of administering antibiotics for septic patients without shock within three hours as opposed to one hour of presentation.  So taking this recommendation into consideration, if a patient were to come in using this study  as a guideline, that patient would have at least a 12% increase in the risk of progression to septic shock by delaying antibiotics up to three hours.  The author also noted that this was the first study to account for the severity of illness  when evaluating the effect of antibiotic delay in patients presenting to the ED with suspected infection.  So this was a major talking point as to why people had thought about removing patients with sepsis without shock from the CMS SEP1 core measures.  And then finally, based on the study, they concluded that the delay of antibiotics is associated with progression to septic shock, with the highest risk being delaying antibiotic  administration up to five hours. And that was clearly seen in the three graphs that we looked at, with the steepest point  on the line graphs being within the first five hours of antibiotic delay. Now the study does not come without its own limitations, the first of which being that  the study was unable to determine the delays in antibiotic administration, and this is largely in part due to the retrospective nature of the study.  And it's also worth noting that lactate was not used as a marker for defining patients with septic shock, and this was because they used both the SEPSIS-2 and SEPSIS-3 definitions,  with the SEPSIS-2 definition not requiring lactate, and the SEPSIS-3 requiring an elevated lactate to define those patients with septic shock.  So the next limitation of the study also being that they were unable to determine the stage of shock that patients were presenting in, as they were not physically in the emergency  department when the patients arrived, and they're having to rely on what was charted in the patient EMR when looking at those patients.  And then lastly, they were unable to determine if patients were unresponsive to fluid resuscitation,  which is something that we often look at to determine if the patient is being diagnosed with septic shock as well.  So some key takeaway points that I was able to take away from this study was that the delay in antibiotic administration actually increases the risk of progression of septic  shock, and we saw that with each hour of delay, this was associated with a 4% increase in the progression of septic shock, and it's important to think about this as we think  about the new guidelines that were just presented to us in this past year. And if we are still being willing to delay antibiotics for up to three hours if a patient  is not currently in shock, we could just be increasing their risk of developing into septic shock, thus leading to poorer outcomes leading down the road.  Also, I'd like to make sure that we think about the patients that are more ill at presentation  are also more likely to develop into septic shock, which just further increases the point of us making sure that we are administering antibiotics as quickly as possible and making  sure that in the patients that are presenting more acutely ill, whether we're using a surge  criteria as recommended by the Surviving Sepsis Campaign or using QSOVA scores in your hospital,  that if a patient is presenting acutely ill, we are making sure that we can minimize the delay in antibiotic administration.  This brings me to my first knowledge assessment question for the day, and that is, does the  delay of antibiotics increase the progression to septic shock based on the results of this study?  And as you can see, based on this study, the answer to this question is yes. It's important to make sure that we are thinking about this whenever we have patients that  are presenting acutely ill and seeing if we can do whatever we can to make sure we're getting these patients their antibiotics as quickly as possible.  This brings me to my second knowledge assessment question for today. So based on the results presented in the study, when is the highest risk of progressing to  septic shock with antimicrobial delay?  And as you can see, based on the results, you all were paying attention and paid attention to the three graphs primarily that I was able to outline, showing that the progression of  septic shock does occur with the highest risk within those first five hours that antibiotics are possibly being delayed.  And with that, I will now open the floor up to any questions. Thank you again for your time and allowing me to present today.  The first question is, for the patients with skin and soft tissue infection, did they break it down for those who had a necrotizing soft tissue infection?  So they did not actually break down if the patients had a necrotizing skin or soft tissue infection.  They did only report the percentage of patients that had a skin or soft tissue infection and  actually ended up labeling it as cellulitis as the most common, and that occurred in 18.6% of the patients that were included in the study.  Do you think including the data from the previous 13 years may have influenced the findings in the study? I think it possibly could have. That's a good point to bring up.  When you're looking at how the time to administration of antibiotics has adjusted over the course  of the 13 years and the couple of renditions to the surviving sepsis guidelines, I think that does play an effect in possibly skewing the data in a way that is more beneficial  for the publishers of this article. So I think it's worth taking that into consideration. However, I still do think it is important, regardless of the severity of illness, that  we're still trying to do our best in making sure we're delaying the time to antibiotics for these patients if we're suspecting that they do have an infection of some sort.  Did they comment at all on the baseline use of steroids? So they actually did not comment on the baseline use of steroids in the study, which would  have been good to know, as we know that the use of steroids can obviously help us in patients that are presenting with sepsis.  However, they did not mention it in the original data that was presented or the supplemental data as well.  And kind of going along with that, did they comment on the second dose antibiotics and the supplemental data?  And if so, how do you feel like this could have affected their primary outcome? They actually did not comment on the second dose, and I think this is, again, possibly  one of the limitations is how little they actually talked about the antibiotics that were used in the trial, as well as doses outside of the timing of the first dose.  So not only did they not mention when the second dose of antibiotics were given, but the only information that they gave about the antibiotics that were given was that they  listed that both Ceftraxone and Piperacillin-Tazobactam accounted for over 90%, but did not give a breakdown of how much or any of the other antibiotics that were possibly used.  So I think this does another confounder that could be looked at for this study in not knowing  exactly what was being used in the study, as well as if patients were found to be septic or even in shock, seeing if the delay in not just the first administration of antibiotics,  but also the second antibiotics could have affected the overall results of the study.  All right, and one final question is, how did the authors define the severe illness in Grubin-Ness trial?  So they did not actually mention how they separated the three groups as far as least moderate and severely ill.  They didn't release the propensity scores, however, they did give the line graph, which I thought was kind of interesting as well, that they gave a great picture, but didn't  go on to break down exactly how ill these patients were. So it could be something that is another confounder as well that could have kind of skewed what  we're able to take away from this study. However, it should be a good study to use as hypothesis generating and making sure that  we're really looking at the patients and what the effect of delay in antibiotics has on the patient outcome as well.  Thank you for your responses, Dr. Ifoy. That concludes our Q&A session.  Thank you to our presenters today and for the audience for attending.  Please join us for our next Spotlight on Pharmacy Journal Club on August 19th from 2 to 3 p.m. Thank you again for joining us. That concludes our presentation for today.

Video Summary

In today's Journal Club Spotlight on Pharmacy webcast, three presenters discussed different topics related to critical care pharmacy. The first presenter, Dr. Heather Wilson, discussed a randomized control trial on the use of vitamin C monotherapy in septic shock. She highlighted previous studies on vitamin C therapy and discussed the results of the trial, which found that continuous infusion of vitamin C did not reduce mortality in septic shock patients. The second presenter, Dr. Sam Markle, discussed a comparison of thrombolytic agents, tenecteplase and alteplase, for the treatment of ischemic stroke. He discussed the potential benefits of tenecteplase over alteplase and presented the results of a study conducted in a mobile stroke unit. The study found that tenecteplase was associated with a faster time to thrombolysis and reduced perfusion lesion volume. The third presenter, Dr. Aaron Ipho, discussed a retrospective cohort study on the timing of antibiotics in septic shock patients. The study found that delaying antibiotic administration increased the risk of progression to septic shock, with the highest risk occurring within the first five hours of delay. The presenters concluded that vitamin C monotherapy is not recommended for septic shock, tenecteplase may be a reasonable alternative to alteplase for ischemic stroke, and early antibiotic administration is important to prevent progression to septic shock.

Asset Subtitle

Pharmacology, Sepsis, Neuroscience, 2022

Asset Caption

"The Journal Club: Spotlight on Pharmacy webcast series focuses on pharmacy topics. This event is held on the third Friday of each month and features lively discussion and in-depth presentations on the latest research.

Heather Wilson, PharmD
Wacker DA, Burton SL, Berger JP, et al. Evaluating vitamin C in septic shock: a randomized controlled trial of vitamin C monotherapy. Crit Care Med. 2022 May;50(5):e458-e467.

Sam Markle, PharmD
Bivard A, Zhao H, Churilov L, et al. Comparison of tenecteplase with alteplase for the early treatment of ischaemic stroke in the Melbourne mobile stroke unit (TASTE-A): a phase 2, randomised, open-label trial. Lancet Neurol. 2022 Jun;21(6):520-527.

Aaron Effoe, PharmD
Bisarya R, Song X, Salle J, Liu M, Patel A, Simpson SQ. Antibiotic timing and progression to septic shock among patients in the ED with suspected infection. Chest. 2022 Jan;161(1):112-120.

Follow the conversation at #SCCMCPPJC."

Meta Tag

Content Type Webcast

Knowledge Area Pharmacology

Knowledge Area Sepsis

Knowledge Area Neuroscience

Knowledge Level Intermediate

Knowledge Level Advanced

Membership Level Select

Membership Level Professional

Tag Pharmacology

Tag Cerebral Ischemia

Tag Shock

Year 2022

Keywords

critical care pharmacy

vitamin C monotherapy

septic shock

thrombolytic agents

tenecteplase

alteplase

ischemic stroke

mobile stroke unit

timing of antibiotics

	Society of Critical Care Medicine 500 Midway Drive Mount Prospect, IL 60056 USA Phone: +1 847 827-6888 Fax: +1 847 439-7226 Email: support@sccm.org	Contact Us About SCCM Newsroom Advertising & Sponsorship DONATE	MySCCM LearnICU Patients & Families Surviving Sepsis Campaign Critical Care Societies Collaborative	GET OUR NEWSLETTER
© Society of Critical Care Medicine. All rights reserved. \| Privacy Statement \| Terms & Conditions The Society of Critical Care Medicine, SCCM, and Critical Care Congress are registered trademarks of the Society of Critical Care Medicine.