Hello and welcome to today's Journal Club Spotlight on Pharmacy webcast, which is supported by the Society of Critical Care Medicine CPP section. My name is Angela Slampak-Sindrick, Critical Care and Emergency Medicine Coordinator and PGY2 Critical Care Pharmacy Residency Program Director at Geisinger Medical Center in Danville, Pennsylvania. I'll be moderating today's webcast. A recording of this webcast will be available to registered attendees. Log into mysccm.org and navigate to the My Learning tab to access the recording. Thank you for joining us. A few housekeeping items before we begin. 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 opinion of the presenter, which may be helpful to others. The views and opinions expressed herein are those of the presenters and do not necessarily reflect the opinions or views of SCCM. SCCM does not recommend or endorse any specific test, position, 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 Ava Gascogne, PGY-2 Critical Care Resident at Boston Medical Center in Boston, Massachusetts. Our second presenter is Kelsey Ladd, PGY-2 Critical Care Resident at Orlando Health, Orlando Regional Medical Center in Orlando, Florida. And our third presenter is Ellen Lee, PGY-2 Critical Care Resident at VA San Diego Healthcare System in San Diego, California. And now I'll turn things over to our first presenter. Hello, everyone. So, again, my name is Ava Gascogne. I am the PGY-2 Critical Care Resident at Boston Medical Center. And today I'll be discussing the ACTS randomized clinical trial, which studied the effect of ascorbic acid, corticosteroids, and thiamine on organ injury and septic shock. Starting off with objectives, today we'll discuss the rationale for the use of hydrocortisone, ascorbic acid, and thiamine in shock, including pertinent literature that has studied this combination. We'll then go into the ACTS randomized trial, analyzing the study and its potential implications in practice. Sepsis is defined as organ dysfunction related to a dysregulated host response to infection. Traditionally, this organ dysfunction has been attributed to a decreased systemic vascular resistance, causing decreased organ perfusion and ultimately impaired oxygen delivery. However, histopathologic analyses of organs after death from sepsis have failed to show substantial ischemic injury and instead some patterns of apoptosis, suggesting alternate mechanisms of organ dysfunction in sepsis. These include mitochondrial dysfunction, direct immune response to infection, microvascular abnormalities, and endothelial dysfunction. Medications that target these non-oxygen delivery dependent mechanisms in sepsis include vitamin C and thiamine, and deficiencies in these two have been described in patients with sepsis and are thought to be due to reduced intake and increased metabolic demand. Corticosteroids in shock have had mixed results but seem to improve shock reversal in patients with sepsis, and the combination of vitamin C, thiamine, and corticosteroids have been evaluated in multiple clinical trials, including Citrus Ali, oranges, and vitamins. The Citrus Ali study looked at vitamin C administration in patients with sepsis and ARDS. No significant drop in SOFA scores or other organ dysfunction markers was seen in this study. Reduction in mortality was noted, however, this was a secondary outcome and the study was not powered to detect a difference here. The oranges trial looked at thiamine, hydrocortisone, and vitamin C, and they actually saw a significant difference in reduction to time to shock resolution without a significant change in SOFA score associated with treatment. However, their primary outcome was originally 28-day mortality and was changed after full data collection. The vitamins trial looked at this combination as well and found no significant differences in time alive and free of vasopressors, which was their primary outcome. Although not powered to detect a difference in this secondary outcome, they did see a significant change in SOFA score with the combination, which leads us into the Axe randomized trial. The Axe randomized trial was a multi-center, randomized, blinded, placebo-controlled trial conducted at 14 centers in the United States. Patients with septic shock were randomized to 1,500 milligrams of vitamin C, 50 milligrams of hydrocortisone, and 100 milligrams of thiamine every six hours for four days or matching placebos in matching volumes. Excluded patients included patients with indications for the study drugs, patients not expected to survive beyond 24 hours, patients receiving renal replacement therapy, pregnant or imprisoned patients, and patients with G6PD deficiency or hemochromatosis. Their primary outcome was change in SOFA score between enrollment and 72 hours. Primary outcomes included kidney failure, 30-day mortality, all-cause mortality to ICU and hospital discharge, ventilator-free days and shock-free days during the first seven days, ICU-free days during the first 28 days, disposition of hospital survivors, 72-hour change in SOFA score components, and delirium on day seven. They estimated that 200 patients were needed to detect a two-point difference in SOFA scores, and this was based on previous literature showing a two-point decrease or more in SOFA scores is associated with approximately a 10% increase in mortality. Two hundred and five patients were enrolled after over 4,000 patients met inclusion criteria. Both groups received a median of two liters of fluids prior to study drug initiation. The median time from vasopressors to initiation of first study drug was about 14 hours. About 45% of patients were mechanically ventilated while about 20% had ARDS, and the median lactate level seen in both groups was about 16 milligrams per deciliter. Baseline SOFA scores were about nine in both groups. This was decreased by 4.7 points with the intervention and by 4.1 points with placebo, the mean difference in reduction being 0.8 points with no significant difference being found. The study did not find any significant differences in kidney failure, 30-day mortality, median shock-free days, or ventilator-free days between groups. They did see a significantly greater reduction in cardiovascular SOFA scores in the treatment group at 72 hours. So the authors concluded that given the combination did not result in a statistically significant reduction in SOFA scores in the first 72 hours after enrollment in patients with septic shock, so routine use of this combination is not supported. The strengths of this study included its design being a multicenter, randomized, placebo-controlled study. Investigators, staff, and patients were all blinded for the duration of the study and baseline characteristics were well-matched between groups. Their dosing scheme reflected those of previous studies. However, limitations of this study include the fact that over 4,000 patients were assessed for eligibility, about 800 were eligible, but only 205 were randomized, potentially implicating selection bias. It's uncertain whether we'd see a difference in the primary outcome if this study medication had been administered sooner. And I think it may have been more interesting to see mortality as a primary outcome as the SOFA score is really just a predictor of mortality. Finally, the study was not powered for subgroup analyses or many of its secondary outcomes, making it difficult to know that whether the difference in cardiovascular SOFA scores that was seen may have been by chance. Although a significant difference was seen in this outcome, it's not necessarily a patient-centered outcome and rather a marker of organ function. So in conclusion, the use of thiamine, vitamin C, and hydrocortisone did not result in a reduction of SOFA scores during the first 72 hours after enrollment in patients with septic shock, and this is another study showing no benefit in the routine use of this combination in septic shock. So my polling questions to the group, the first one, with the results of this study and taking into consideration all previous studies regarding ascorbic acid and thiamine and steroids for sepsis, do you think future research is warranted in this area? So it looks like 73% of you said no and about 20% of people said yes. I think I agree with the group that is going with no. I think we have quite a few studies now that suggests that this combination is not beneficial in septic shock. There was a study done in the SCCM Journal Club last month that asked if people had or had not implemented this therapy in their hospital and or institution and many people said no. So my question today is why has combination therapy with ascorbic acid, thiamine, and hydrocortisone not been adopted at your institution? And it looks like majority of people say lack of efficacy. So, with that, I can take any questions. Thank you, Ava. We do have some questions coming from the attendees for the webinar today. First up, how did the severity of illness of study patients compare between all of the trials you reviewed with us today? I think that the SOFA scores in this study compared well with previous studies. These patients had SOFA scores of about nine, correlating with about a 30% risk of mortality. I would have liked to see the vasopressor doses that patients were getting because I think that this was an important point made in other studies that could have been useful in determining the severity of illness in this study compared to previous studies. Thank you for sharing that. Our next question relates to your polling question. The question is, so can we put this triple cocktail to rest or is there still a patient population that may benefit? I personally think it would be interesting to see a study in patients who are septic and not yet in shock to see if early intervention potentially reduces progression to shock states. However, I think that I have personally seen enough in patients with septic shock and I think that we do have enough data to say that this the routine use is not supported. Thank you. That would be an interesting patient population to explore. Do you feel that the results of the study you've presented today would have been different if perhaps a different dosing schematic was used or a different dosing of the three key pieces of the therapy? I do not. I think that the dosing regimens are what have been reported in previous studies and previous studies have looked at serum concentrations of vitamin C and thiamine and have reported that these concentrations are adequate in serum. Thank you. Our final question, how do you feel about Dr. Merrick's argument that most studies have taken too long to administer vitamin C, which relates back to your former thought about an unexplored patient population potentially for future studies? Yes, I think that there is the potential and I do think it would be interesting that possibly if we do administer it earlier that this therapy could possibly help with progression into shock, which has not really been studied in any of the studies so far. Thank you, Ava. That concludes our Q&A session. Now I'd like to introduce our second presenter, Kelsey Ladd. Hi, everyone. Thank you for allowing me the opportunity to present today and for joining in. My name is Kelsey Ladd and I'm one of the current PGY-2 critical care pharmacy residents at Orlando Regional Medical Center. Today, I'll be reviewing the low-chloride versus high-chloride containing hypertonic solution for the treatment of subarachnoid hemorrhage-related complications, or the acetate trial. To begin the background regarding the use of hyperosmolar therapy for the management of elevated intracranial pressure, or ICP, this therapeutic strategy remains to be one of the mainstays in treatment for acute brain injuries. Hyperosmotic agents work by increasing the serum concentration or osmolality in order to create a concentration gradient to draw water from the brain parenchyma into the plasma. The two main hyperosmolar agents utilized in clinical practice remain to be hypertonic saline and mannitol. While no difference in patient functional outcomes or mortality have been seen between these two agents, improved ICP control and brain tissue oxygenation have been suggested with the use of hypertonic saline when compared to mannitol. However, some concerns still remain with the use of hypertonic saline. Hyperchloremic acidosis-induced acute kidney injury, or AKI, is one of the most common concerns associated with the use of hypertonic saline, along with hyperkalemia, impaired perfusion, and increased coagulopathy, which have also been animal studies. Increased levels of serum chloride leads to decreased amount of chloride resorbed in the proximal tubule and loop of Henle, leading to increased levels of chloride in the distal tubule. Increased chloride levels then leads to the release of vasoactive mediators, resulting in vasoconstriction of the afferent arteriole. This ultimately causes a decrease in glomerular filtration rate and AKI. Specifically, acute kidney injury has been shown to be associated with poor clinical outcomes, notably an increased risk of morbidity and mortality in patients with subarachnoid hemorrhage. To review some previous literature evaluating these events, we will be looking into the SALT-ED and the SMART trials. These trials are massive multiple crossover trials which compare the outcomes of normal saline to that of balanced crystalloids. The SALT-ED trial specifically looked at adult patients who had received isotonic crystalloids in the ED who were not admitted to the ICU, which ultimately found a decreased rate of adverse kidney events defined as death, new-onset renal replacement therapy, or a doubling of serum creatinine from baseline in patients who received balanced crystalloids in comparison to normal saline, with a number needed to treat of 112. The SMART trial, on the other hand, looked at the outcomes of critically ill patients and found similar results with significantly decreased major adverse kidney events in patients receiving balanced crystalloids, with a number needed to treat of 91. Of note, this outcome in the SMART trial was largely driven by a one percent reduction of mortality seen with the use of balanced crystalloids versus that of normal saline. This brings us to our first polling question. Which agent does your institution most frequently utilize for hyperosmotic therapy in the setting of acute brain injury? All right, so it looks like a majority of institutions said the hypertonic sodium solutions, which is very similar to what we utilize here at Orlando Regional. We do have order sets, however, available with hypertonic saline, 50% chloride and 50% acetate for both our 7.5% and 3% solution concentrations. This leads us to the study we'll be discussing today, low chloride versus high chloride containing hypertonic solution for the treatment of subarachnoid hemorrhage related complications, or the acetate randomized trial, which was published in May 2020 in the Journal of Intensive Care. The acetate trial sought to assess the feasibility, safety, and the effectiveness of hypertonic sodium chloride versus hypertonic sodium chloride sodium acetate to treat cerebral edema and elevated ICPs in patients with aneurysmal subarachnoid hemorrhage. This trial was a single-center, double-blinded, double-dummy pilot design. Adult patients with the diagnosis of aneurysmal subarachnoid hemorrhage were included, however, patients were not randomized unless they received hypertonic saline therapy for the acute treatment of cerebral edema or elevated intracranial pressure, as well as had a serum chloride level of at least 109 millimoles per liter following that treatment. Patients were excluded if they were considered to have a poor prognosis such as diagnosis of brain death or probable withdrawal of care, or if they had a previous diagnosis of end-stage renal disease requiring dialysis treatment. Patients were randomized in a one-to-one ratio to receive hypertonic sodium chloride or a hypertonic sodium chloride and sodium acetate mixture and were stratified by admission serum creatinine in Hunt and Hess score. The trial utilized the double-dummy method due to volumetric variation in the hypertonic solutions with plasmalite, a balanced IV crystalloid solution being utilized for all other IV fluids administered apart from the carrier solutions for IV medications. When comparing the two IV fluid interventions, the commercially available 30 milliliter 23.4% sodium chloride was used in the hypertonic sodium chloride arm, which contains 120 milliequivalents of both sodium and chloride and provides an expected increase in serum sodium and serum chloride of approximately 2 to 3 milliequivalents per liter in an average-sized patient. For the hypertonic sodium chloride and sodium acetate fluid, a slightly lower concentration was created and a slightly higher volume was used. However, this provided a higher amount of sodium per dose at 140 milliequivalents and a balance of chloride and acetate at 80 and 60 milliequivalents respectively. This solution provided an expected increase in serum sodium of about 3 to 4 milliequivalents per liter and serum chloride of about 1 milliequivalent per liter. The primary outcome of the acetate trial was the change of serum chloride concentration between pre-randomization and the highest result following it during admission. Secondary outcomes assessed included new onset AKI, incidence of in-hospital mortality, and treatment effect for intracerebral hypertension. The study team intended to randomize 60 patients for this pilot trial with 30 patients per group to have a 63% power to detect a six-point difference in the change of serum chloride levels between the treatment groups based on retrospective data from the institution. Continuous data was analyzed utilizing two-sample t-tests or ANOVA with post-hoc SHEF tests, while categorical data was analyzed using a Pearson chi-squared test. A univariate logistic regression analysis was utilized to assess risk factors associated with AKI. When looking at the patient selection for this trial, it's important to note while 59 total patients were consented to be included for the trial, only 44 of these patients required the receipt of hyperosmolar therapy for the treatment of elevated ICP or cerebral edema, and only 32 of those patients had a documented serum chloride level of at least 109 millimoles per liter, which then made up the randomized patient population. Overall, the baseline characteristics between the two randomized treatment arms were well-matched with no statistically different characteristics between them, with the average patient being about 53 years old, predominantly female, and with an admission Hunt and Hess score of 3 to 4 and serum creatinine of 0.8 mg per deciliter. Patients who were not randomized, however, did notably have a slightly higher GCS score as well as lower Hunt and Hess scores, which likely relates to the fact that over 50% of these patients did not require the receipt of hyperosmolar therapy. Following randomization, which occurred on approximately three days post-admission in both treatment arms, the baseline serum sodium and serum chloride in each group were approximately 142 and 112 millimoles per liter, respectively. Looking into the primary outcome, while the change in serum chloride was significantly higher at an average of 3.3 millimoles in the sodium chloride group versus 1.6 millimoles per liter in the sodium chloride-sodium acetate arm, this difference did not meet statistical significance. The average serum chloride level in both groups during their ICU stay was also not significantly different between the groups at a level of 106 millimoles per liter. When looking at the sodium chloride and sodium acetate treatment arm, overall had higher values for change in serum levels during their ICU admission, change per dose, and average serum levels, with the change in serum sodium per dose being significantly higher in this arm at 2.2 versus 1.4 millimoles per liter. Finally, the change in bicarb serum was also significantly higher in the sodium chloride and sodium acetate arm. However, average serum levels did not differ significantly between the two groups. When looking to additional outcomes, it's important to note that there was not a statistically significant different amount of doses administered per day of hypertonic therapy between the groups, which was measured throughout their ICU stay and was similar in both groups at 23 days. Intracranial pressure reduction was also similar between the groups at both 20 and 60 minutes following dose administration, with an approximate 64% reduction in ICP at 20 minutes and 56% reduction in ICP at 20 minutes after. Finally, there were significantly more acute kidney injuries in the sodium chloride group when compared to those who received sodium chloride and sodium acetate, with a number needed to treat of three with the use of the balanced solution to prevent one AKI. It's important to note, though, that only two AKIs in the sodium chloride group and none in the sodium chloride-sodium acetate group occurred post-randomization, showing that the majority of AKIs occurred within the first three days following admission and after receipt of strictly hypertonic sodium chloride therapy. No significant difference in additional clinical outcomes was identified between the two groups, including incidence of vasospasm, delayed cerebral ischemia, ICU length of stay, 90-day survival, and levels of urine AKI biomarkers, with the exception of Kim-1 concentrations, a marker for proximal tubular injury on day 5 post-admission being significantly higher in those treated with strictly hypertonic sodium chloride. Following a univariate logistic regression analysis to assess correlation with clinical parameters in AKI, the odds of AKI with treatment with hypertonic sodium chloride and sodium acetate was 82% less likely, while a change in serum chloride level was associated with a 32% higher risk. However, it's important to keep in mind this univariate analysis is exploratory in nature and did not control for additional confounders for the development of AKI. This analysis identified potential risk factors, which may be included in future multivariate regression, to determine independent risk factors for AKI. The authors' cases of this pilot trial showed the feasibility and safety of replacing 23.4% sodium chloride infusions with a chloride-lean 16.4% sodium chloride-sodium acetate infusion to treat cerebral edema in patients with subarachnoid hemorrhage, and that the more balanced infusion was associated with lower AKI rates, while still showing a similar effect on ICP reduction. Moving into article critique, some strengths of this trial include the randomized double-blind double-dummy design, which reduced the risk of bias within the study. The authors also assessed clinically relevant outcomes, including complications associated with subarachnoid hemorrhage, as well as ICU length of stay and mortality. Some limitations include the small sample size and subsequent lack of power, which could have prevented finding a difference in the primary outcome, even if one did exist. Furthermore, patients' overall fluid status was not reported within the treatment groups, which may have affected electrolyte outcomes as well as AKI risk between the two groups. Finally, patients were only included following a serum chloride level of at least 109 millimoles per liter and the receipt of hypertonic sodium chloride solution, which filtered out patients at higher risk for AKI, making it difficult to generalize these results to patients at admission with initial receipt of balanced hypertonic saline therapy. This brings us to our second polling question. On the results of this trial, will you be more likely to utilize hypertonic sodium chloride-sodium acetate for the hyperosmolar therapy at your institution? All right, so it looks like it's about a 50-50 split, which is very interesting to me. Currently at our institution, we typically do not utilize the sodium chloride, sodium acetate treatment arm until they do have these increased levels of serum chloride. So my overall conclusion of this trial is that a balanced hypertonic saline solution appears to be a reasonable strategy for the treatment of cerebral edema or elevated ICP in patients with aneurysmal subarachnoid hemorrhage at risk for AKI. The balanced hypertonic solution showed similar decrease in ICP, as well as the potential for decreased risk of AKI in these patients when compared to hypertonic sodium chloride. However, methodologic choices, including the delayed randomization following the receipt of hypertonic sodium chloride therapy, with majority of AKIs occurring in the timeframe prior to patient randomization, prevents the application of these results to patients with aneurysmal subarachnoid hemorrhage early in their disease course. Further randomized controlled trials, which are adequately powered, are needed to assess the true clinical benefit of a balanced hypertonic solution in comparison to sodium chloride therapy. That concludes my presentation evaluating the acetate trial, and at this time, I'd be happy to answer any questions you all may have regarding the trial. Thank you for your presentation. At what serum sodium, or rather, at what serum chloride level would you recommend switching patients from 23.4% hypertonic saline solution to the sodium chloride, sodium acetate combination solution? So typically at our institution, we do wait until patients do experience these elevated serum chloride levels, typically of at least about 110 is what we see in clinical practice as far as when we start to utilize the balanced solution over the sodium chloride solution. Thank you. At your institution and nationally, is the sodium chloride acetate solution and nationally, is the sodium chloride acetate combination product something that is compounded, or is it commercially available? If it is not commercially available, how would you navigate the potentially increased pharmacy IV room workload that would come with the need to compound this medication? Yes, that's a good question. I definitely think that's one limitation of this therapy and why we typically don't see it utilized as a first-line therapy in terms of immediate ICP reduction since the 23.4% sodium chloride is commercially available and that any of these balanced solutions are going to have to be compounded and therefore increase risk of IV room error as well as potential time until the patient can actually receive this acute therapy. So I do definitely think that is a limitation of this treatment as well. Thank you. Did the investigators look at differences in contrast loads between the two groups? No, so I do think that's another limitation of this trial is that they actually did not really mention any sort of other medications or any other aspects which may have contributed to an increased risk of acute kidney injury. So they really only analyzed just these two therapies and not any additional medications. Thank you. Would you expect different outcomes if the investigators had used a 3% continuous infusion rather than the 23.4% bolus? Yeah, so what I did find interesting is that they went with the 30 milliliters and 50 milliliters, just overall very small volume treatment just because we would only expect to see an increase in sodium or in serum chloride levels of about one to maybe three milliequivalents per liter. So I think if they did use a treatment maybe such as the 7.5% or the 3% either as a bolus formulation or as you mentioned, the 3% continuous infusion, I think we potentially could have seen a difference in the serum chloride levels which was the primary outcome of this trial. Thank you. And it sounds like at your institution you're utilizing both mixed solutions as well as the straight sodium chloride containing solution. Given that these are both high risk, high alert medications and that you're utilizing multiple concentrations with multiple components, what are some of the safety steps that you have in place for both the pharmacy department as well as nurses administering these medications on the floor to ensure that there aren't any pharmacotherapeutic mix-ups? So we do compound, like I said, the 7.5% as an equal 50-50 split and the 3% solution as a bolus and a continuous infusion as a 50-50 split. So we definitely have this as a high alert and have training for our IV room pharmacists to be aware that these are the concentrations that we are available to compound here at our institution. However, from a nursing standpoint, I have not heard of much kind of questioning or concern as far as the difference between the sodium chloride and the sodium chloride acetate solutions when they are administering these to the patients as far as any sort of difference in how we would approach these therapies from their standpoint. That concludes our Q&A session. Thank you, Kelsey Ladd. Now I'd like to introduce our final presenter, Ellen Lee. Hi, everyone. My name is Ellen Lee. I'm the PGY-2 Critical Care Pharmacy resident from VA San Diego. And today I'll be presenting on the article, The Effect of Dexmedetomidine on Vasopressor Requirements in Patients with Septic Shock, a Subgroup Analysis of the SPICE-3 Trial. I have nothing to disclose. And to start things off, we have our first polling question. What is the most common sedative agent used at your institution in patients with septic shock who require mechanical ventilation? Dexmedetomidine, propofol, benzodiazepines, or ketamine? Okay, looks like a majority of institutions use Propofol. That is what is most commonly seen here as well at the VA. Great, to provide some background for this study, it's important to recall that septic shock is characterized by a significant decline in vascular response, and our bodies help to compensate by activating our sympathetic nervous system. However, sometimes extra support via pressors may be needed, and while initially this surge of sympathetic activity is helpful, at some point, prolonged sympathetic response can have detrimental effects. For example, the extra amount of catecholamines can lead to hyposensitivity or downregulation and desensitization of our alpha-adrenergic receptors, and that overall can lead to a reduced response to vasopressors. This is where studies have come into play looking at central alpha-2 agonists in possibly helping mitigate this sympathetic surge, and while this approach may seem counterintuitive due to the potential hemodynamic side effects, some experimental animal models in sepsis as well as some human studies have shown that agents such as clonidine and dexmedetomidine can actually help lower vasopressor requirements and increase responsiveness. There are some hypotheses out there regarding the mechanism of how this is working in sepsis, but the main ones that I've included here are that it reduces sympathetic outflow, possible anti-inflammatory effects, and it exerts some action on the local vasculature and smooth muscle cells. All these basically try and help mitigate that surge in sympathetic response to help with preventing downregulation and helping to resensitize adrenergic receptors. A brief literature review shows that this idea of using some sort of sedative agent in lowering vasopressor requirements was done in 2016 by Marler et al., and instead of dexmedetomidine, they looked at continuous IV propofol for sedation versus non-propofol. In terms of their primary outcomes, they looked at vasopressor support requirements, a greater than 20% decrease in MAP from baseline as well as hospital mortality, and what they found was that propofol essentially did not increase vasopressor requirements as none of these outcomes were statistically significant. A more recent study done in 2018 by Marler et al. looked at patients on propofol and remifentanil at baseline. Propofol was then replaced with dexmedetomidine, and then four hours later, patients were switched back to propofol, and their primary outcome was norepinephrine mean dose. And so at baseline, the mean dose was around 0.69 mics per kilo per minute, and after replacing the propofol with the dex, it halved the requirements to 0.3. Later on, after switching back to propofol, vasopressor requirements did increase, although not all the way back to baseline levels. And so their conclusion was that dexmedetomidine helped lead to decreased catecholamine requirements with a comparable level of sedation. That brings us to our study today, which was published in July of 2020 in Critical Care. The objective of the study was to assess the physiological effects of dexmedetomidine on vasopressor requirements and blood pressure in the first 48 hours after randomization. This was an exploratory post-hoc retrospective subgroup analysis of septic patients, and data was collected and analyzed from two hospital sites in Australia and Switzerland. And the intervention was essentially early dexmedetomidine for sedation versus usual care, which was propofol, midazolam, or another sedative agent. To summarize some of the main inclusion and exclusion criteria, in terms of inclusion, patients had to essentially meet SIRS criteria, be recently intubated and sedated for less than 12 hours before randomization, and be treated with continuous vasopressors or inotropes for more than four hours before randomization. The major exclusion criteria included patients with brain injuries, overdose or burn admissions, current neuromuscular blockades, pre-low mass of heart rate, and acute fulminant hepatic failure. The primary outcome in this study was median vasopressor dose in the first 48 hours expressed as a noradrenaline-equivalent dose, otherwise abbreviated as NEQ, and I've listed the equation that they kind of used to basically standardize against the vasopressor doses. And this was adapted from the ATHOS-2 trial. And other secondary outcomes included cumulative and peak NEQ dose, change in NEQ dose from baseline to peak dose, as well as the ratio of NEQ to MAP. Other exploratory outcomes included cumulative duration of vasopressor support, mortality, duration of mechanical ventilation, and length of stay. For baseline characteristics, the mean age was around 62 to 67 years old in primarily male patients. The Apache-2 scores were generally around 25. Time from ICU admission to randomization ranged from 8 to 11 hours, whereas the median start time of vasopressors was around 1.4 to 2.7 hours. The only statistically significant variable in this first set of baseline characteristics was the coagulation component of the SOFA score, which was significantly different in the usual care group. In terms of other baseline characteristics, norepinephrine was the main pressor being used at baseline, and propofol and fentanyl were the main sedative and analgesia agents. There were no significant differences seen in patients on CRRT or with hydrocortisone use for septic shock. The only other significant variable here is creatinine, which was significantly higher in the usual care group compared to the DEX group. And then lastly, in terms of baseline, median, nor equivalent dose, they were not significantly different. This graph here shows our primary outcome result, which was the median NEQ dose compared from the control in blue and DEX group in orange. And while the DEX appears to be lower, in the first 48 hours after randomization, essentially, there was no significant difference seen between the two groups with a p-value of 0.054. Moving on to our secondary outcomes, there was, again, no significant difference seen in cumulative NEQ dose, peak NEQ dose, or relative change in NEQ dose from baseline to peak level. Where they did find some significant difference was when they looked at the NEQ to MAP ratio and adjusted it for different covariates, such as admission diagnosis, CRRT, or hydrocortisone use. And essentially, what they found was that vasopressor requirements to maintain the target MAP were lower in the DEX group, with a p-value of 0.02. Lastly, to finish off the results, there was no significant difference seen in their exploratory outcomes, which included duration of vasopressors or mechanical ventilation, as well as ICU length of stay or hospital ICU mortality. In terms of adverse effects, though, the DEX group did see significantly more hypotension than the usual care group, with seven cases versus one case in the usual care group. The authors' conclusions were that patients in the DEX group received similar vasopressor dosing in the first 48 hours to usual care. And upon their adjusted analysis, it showed that DEX appeared to be associated with lower vasopressor requirements to maintain target MAP. For strengths of this study, I thought the baseline characteristics were overall relatively well-matched between the two groups. A minimum of 38 patients were needed per group for greater than 90% power, which they did achieve. And the authors did do an adjustment for their secondary outcome, looking at the NEQ over MAP ratio, which would help in trying to reduce any sort of confounding factors. Additionally, I do believe it helps add to the body of literature regarding the potential hemodynamic effects of DEX. In terms of limitations, though, these patients were newly intubated and only followed for 48 hours after randomization, making it difficult to extrapolate these results in more severely ill patients that could potentially benefit from an increased pressor response. Additionally, it doesn't really give us any information on patients who may have refractory pressor requirements but are not intubated. Additionally, this was an open-label design two-center retrospective trial, so that may limit generalizability between different sites. It's also unclear from the results what the optimal dose of DEX would be to kind of cause this effect in increased vasopressor response. Additionally, there was no standard protocol for sepsis or hemodynamic management, which could provide as a confounding variable due to possible differences in treating antibiotics or other sepsis protocols and things like that. And lastly, the percentage of RAS scores were less than negative 2 on study day 1 was higher in the usual care group than the DEX group. And that could potentially mean that patients in the usual care group were more sedated at baseline, which may have affected some of the outcomes, making DEX appear better than the usual care group. So based on the data presented in this article, how inclined would you be to initiate DEX in a septic patient to decrease vasopressor requirements? Okay, so a majority of 85% answered no change in current practice, which is what we have decided to do as well here at the VA with the information. And so for key takeaway points, in patients with septic shock without worsening hemodynamic instability, I do believe DEX still remains as a potential option for sedation. I think what this article did show is that DEX didn't necessarily lead to increased pressure requirements, but I do believe the overall effect on lowering pressure requirements does remain exploratory, and we still need more research out there before any changes in current practice can be implemented. Lastly, there are some future studies in process. There's currently a French trial called the Address Pilot Study that's recruiting to try and see if DEX can reduce vasopressor requirements in patients on phenylephrine. So that might be the next big trial to kind of evaluate the evidence. And with that, I will be happy to take any questions. Thank you so much, everyone, for the opportunity to present. Thank you, Ellen. Our first question from the group is, how do you collect hypotension in a group of patients on vasopressors? Sure. In that scenario, it may be up to looking more at a MAP goal, I believe. In terms of this study, they did not have a set standard or protocol on how they reported or collected adverse effects, which could be a limitation. So if there are no set protocols or anything like that, it may indeed affect the adverse effect outcomes. And maybe DEX may not be any more different than the usual care groups. So that might be hard to say. And it would be interesting in future studies to see if there was a more standardized way of collecting adverse outcomes, if DEX does indeed cause more hypotension than other sedative agents. Thank you. When studying these medications, patients may require rescue therapies for breakthrough agitation during administration of the DEX metatomidine. Which agents would you recommend to be utilized for breakthrough agitation in light of the current study? So for breakthrough medications, at least in this study as well as the SPICE-3 trial, they used a range of different medications such as your usual like antipsychotics, like IV Haldol. And primarily antipsychotics were used. They may consider not using like IV midazolam or anything like that if patients were using that as their sedative agent. I do know that DEX metatomidine has shown to reduce delirium compared to IV benzos. And so this agent may be preferable in a patient population with septic shock who may be delirious as well. So this may be sort of the patient population that you might want to consider using DEX in as well. Thank you. That concludes our Q&A session. Thank you again to Ellen for presenting. Thank you to our presenters today and the audience for attending. Please join us on the third Friday of the month from 2 to 3 PM Eastern Standard Time for the next Journal Club Spotlight on Pharmacy. That concludes our presentation today. Thank you.

critical care medicine

ACTS trial

organ injury

septic shock

SOFA scores

acetate trial

hypertonic solutions

vasopressor requirements

dexmedetomidine