SCCM Resource Library-April 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 Stephanie Lombardi, Critical Care Pharmacy Specialist in Cardiothoracic, Vascular, and Surgical ICU at Cleveland Clinic in Cleveland, Ohio.  I will be moderating today's webcast. A recording of this webcast will be available to registered attendees.  Log into myfccm.org and navigate to the My Learning tab to access the recording. A few housekeeping items before we get started. There will be a Q&A after each of today's speakers.  To submit questions throughout the presentation, type into the question box located on your control panel.  You will also have the opportunity to participate in several interactive polls. When you see a poll, simply click the bubble next to your choice.  You may also follow and participate in live discussion on Twitter following fccmcppjc and 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. Our first presenter today is Jessica Hu, PGY-2 Critical Care Resident at Hospital of the  University of Pennsylvania in Philadelphia, Pennsylvania. Our second presenter is Lydia Ware, PGY-2 Critical Care Resident at Brigham and Women's Hospital in Boston, Massachusetts.  And our third presenter is Alyssa Lear, PGY-2 Critical Care Resident at Medical University of South Carolina in Charleston, South Carolina.  And now I'll turn things over to our first presenter.  Good afternoon, everyone. My name is Jessica. I am the second-year Critical Care Pharmacy Resident at the Hospital of the University of Pennsylvania.  And today I will be presenting the ProMedIC trial looking at prophylactic melatonin for delirium in intensive care.  Delirium is described as an acute and or fluctuating change in a patient's neurological and behavioral function from their baseline.  If left untreated, it can lead to worsening patient outcomes and permanent cognitive impairment, resulting in increased morbidity and mortality.  There are many risk factors for experiencing delirium in the intensive care unit or ICU, one of them being sleep disruption.  Poor sleep is one of the most common stressors experienced by critically ill patients, as there are many disruptions that can impact their sleep-wake cycle and increase their  risk of delirium development. As a result, a sleep-promoting, multi-component protocol has been incorporated as one of the  many non-pharmacologic strategies in the ICU liberation bundle. Melatonin is known to be an important neurotransmitter in regulating the body's sleep-wake cycle  and circadian rhythm. Lower serum melatonin concentrations have been reported in patients with delirium, suggesting supplementation with exogenous melatonin may be beneficial.  However, there are mixed findings regarding its efficacy in delirium prevention, and therefore  the 2018 Pain, Agitation, and Delirium, Inability, and Sleep Disruption Guidelines make no recommendations  regarding its use in sleep improvement and delirium prophylaxis in the ICU. Here is a quick visual of melatonin production and secretion for your reference.  During hours of darkness, endogenous melatonin is produced by the pineal gland and reduces the wake-promoting signal from the suprachiasmatic nucleus.  Sleepy concentrations are seen around 2 a.m. and slowly decline as more daylight is present. Alterations to sleep disrupt the circadian cycle, resulting in reduced concentrations  and impaired sleep quality. I would like to highlight a few trials that looked into melatonin utilization in delirium prevention and sleep improvement.  Bourne and colleagues performed a single-center, randomized controlled trial looking at melatonin in 10 mg daily versus placebo, and found there was better nocturnal sleep reported,  but also supraphysiologic melatonin concentrations that remained elevated during the day. These results suggest that the starting dose utilized may have been too high and lower  doses may suffice for improving sleep quality. Our online colleagues studied melatonin 0.5 mg daily versus placebo in internal medicine  patients and reported a lower risk of delirium with melatonin use. However, this does not reflect an ICU patient population experiencing delirium.  De Jong and colleagues studied the use of melatonin 3 mg in elderly patients undergoing hip surgery, and found there was no difference in the incidence of delirium when compared  to placebo. And a recent multi-center, randomized controlled trial by Gandolfini and colleagues studied  the use of melatonin 10 mg in adult patients admitted to medical and surgical ICUs, and found while there was improvement in sleep quality, there were no differences in delirium  occurrence when compared to placebo. Serum concentrations of melatonin were measured and showed appropriate peaks in melatonin  levels around 2 a.m., and elevated concentrations persisted until 12 p.m. While this most recent trial accurately reflects the general ICU patient population, you can  see there's still conflicting evidence surrounding melatonin's effects in delirium prevention given the variation in dosing schemes and sample sizes.  Therefore, the authors of the PRO-MEDIC trial aimed to determine if early administration of melatonin would be effective in reducing delirium in critically ill patients.  The PRO-MEDIC trial was a multi-center, randomized, double-blind, placebo-controlled trial performed in 12 ICUs in Australia from July 2016 to September 2019.  Patients received either melatonin 4 mg or a placebo daily at 2100 as a liquid formulation via a gastric tube for 14 consecutive nights or until IC discharge.  This dose was chosen based on prior studies evaluating doses ranging from 0.5 to 10 mg. Serum melatonin concentrations were measured 2 to 3 hours after administration in a subset  of patients to ensure adequate melatonin absorption. Open-label melatonin use was discouraged and considered a protocol violation, and all other  care was at the treating clinician's discretion. Patients were included if they were 18 years or older, required ICU admission with an expected  length of stay greater than 72 hours, and enrolled within 48 hours of their ICU admission. A full list of exclusion criteria is listed here, but I will highlight the most relevant  ones being those who were already receiving, were at prior hypersensitivity reactions to melatonin, or had no enteral access.  The primary outcome of the PRO-MEDIC study was the difference in the proportions of delirium-free assessments based on the confusion assessment method for ICU, or CAM-ICU score.  Scores were measured every 12 hours and on all assessable patients. Training was provided to clinical staff who were unfamiliar with this tool.  Key secondary outcomes included delirium-free and delirium-and-coma-free days, patients without delirium or coma, delirium severity measured by the CAM severity score, sleep  quality measured through Richard Campbell's sleep and Little's questionnaires, ICU and hospital length of stay, duration of mechanical ventilation, and 28-day and 90-day mortality.  A priori subgroups were also assessed to determine if any specific patient populations would  benefit from melatonin use, and these included age, gender, diagnostic category and type, pre-deliric score, and baseline delirium.  All serious adverse events, including morbidity and mortality, were defined and reported, and liver function tests were measured at baseline and at day 5.  For the statistical analysis, the authors calculated that a total of 734 patients were needed to achieve 80% power and a 10% absolute decrease in delirium-free assessments, but  the sample size was increased to account for any potentially missing data from those who were lost to follow-up. A p-value less than 0.05 indicated statistical significance.  Univariate logistic regressions were utilized for categorical variables and for the differences in length of stay for the secondary outcome.  The primary outcome was assessed using Mann-Whitney U-Test, and 90-day mortality was analyzed using a cost-proportional hazard model, McCabe-Meier-Kurt.  Transitioning into the results of the study, baseline characteristics between the two groups were similar. Most participants were male with an average age of around 62 years.  Around 9% of participants were CAM positive at baseline and were at moderate risk of developing delirium within 24 hours of ICU admission based on their pre-deliric score.  Confirmation of steady drug absorption was assessed based on serum concentrations, and these reported levels are similar to what have been published in other melatonin studies.  Around 7% of total steady drug doses were missed or not given, and no adverse drug events were reported throughout the study.  For the primary outcome of proportion of delirium-free assessments per patient, there was no statistically  significant difference between the two groups, with 79.2% noted for melatonin and 80% for placebo.  Attempted delirium assessments were done for 82.9% of all available time points, and of the attempted assessments done, around 19% of assessments were not possible due to presence  of coma. Reasons for missed assessments included forgotten assessments or patient unavailability due to procedures.  The median number of assessments was 5 for melatonin and 6 for placebo, highlighting that patients' ICU length of stay was shorter than the maximum 14-day timeframe.  Non-pharmacologic therapies utilized for delirium prevention, such as physiotherapy, mobilization,  and transport, were done at clinicians' discretion, but there were no differences noted between both groups.  I will note that other non-pharmacologic treatments noted in the ICU liberation bundle,  such as use of visuals and hearing aids, music, family engagements, or minimal, were not reported at all.  The AYRI analysis for the average percentage of delirium and coma-free assessments also showed no statistically significant differences, with the exception in the age group of 18-64  years. This is an interesting finding noted by the authors with hypothesis-generating potential.  Also interesting to note is that regardless of patients' possible risk of delirium at baseline with the predeliric scoring tool, there were no differences seen between melatonin  use versus placebo. There were no statistically significant differences seen for any of the secondary outcomes, but  there are a few outcomes I would like to bring to the audience's attention. Antipsychotic and sedatives were used around 20% and 60% in both groups respectively, with  the lansipine and getipine being the two most common antipsychotics, and propofol and fentanyl as the two most common sedatives used.  The mean ICU length of stay was 5 days for both groups, and when we think back to the median number of delirium assessments performed, this confirms that patients were in the ICU  for a relatively short period of time, which could have impacted the overall effect of melatonin seen in this study.  Lastly, the estimated hours of sleep in the ICU was extremely poor, with a mean duration of about 4 hours in both groups.  Both observed and reported sleep ratings based on the RCSQ and the Littles questionnaires were low, highlighting truly how disruptive and uncomfortable it is for patients to be  in the ICU. Based on the results, the authors concluded that the use of melatonin did not reduce the  prevalence of delirium in critically ill patients when compared to placebo, and there were no  subgroups with the exception of the age group of 18 to 64 years seen to benefit with melatonin.  Sleep quantity and quality in the ICU remained poor based on reported and anecdotal evidence. When assessing the strength of the study, this was the largest double-blind randomized  controlled trial for melatonin to date, which increases generalizability of these results. Serum melatonin concentrations were used to assess for adequate absorption, and confirmed  that the 4 mg dose would achieve appropriate concentrations within the body. Another strength of the study was the use of subgroups to identify potential patient  populations that may benefit from melatonin. Regarding limitations of the study, the percentage of missing delirium assessments surpassed what was anticipated.  The authors noted that CAM-ICU assessments were not routine practice at most study sites, which likely contributed to the number of missing delirium assessments.  While there are other validated delirium assessment tools available, CAM-ICU is a well-known and  established scoring tool, and so I'd be interested in knowing what were the routine practices at these study sites in assessing delirium.  And when we assess for delirium, there are different classifications, such as hypoactive, mixed, and hyperactive delirium.  Because there were no RAS scores reported, we are unable to differentiate a patient's delirium subtype in the study, and therefore unable to further assess melatonin's potential  role in mixed or hyperactive delirium. In terms of non-pharmacologic strategies utilized, there was a range in usage overall, given that these interventions were not protocolized.  However, there were no statistically significant differences between both groups. Lastly, short ICU length of stay and poor estimated sleep duration could have impacted  the author's ability to assess for maximum clinical benefit. It would be interesting to see if the outcomes of the studies would have been different in  patients at higher risk of delirium at baseline, who had longer ICU length of stays, and had an optimized sleep environment.  My personal takeaway from the PROMEDIC trial is that melatonin likely does not prevent ICU delirium, but can still be incorporated with other preventative strategies.  Given that it has such a favorable adverse effect profile, melatonin would not provide harm, and I would feel comfortable recommending this if patients or patient care teams are  requesting something for sleep. While the study confirms that the 4-milligram dose provides adequate serum concentrations  and absorption, there still may be utility in studying higher doses under 10 milligrams. If a patient were to be initiated on melatonin, I would likely start at 5 or 6 milligrams,  given its low risk of toxicity. Lastly, I believe that improving sleep quality by maximizing my non-pharmacological agents  would give me the biggest bang for my buck in minimizing delirium risk. No pharmacological agents have consistently shown benefit in preventing delirium, so I  believe the focus should shift towards finding a holistic approach in improving sleep in these critically ill patients.  For my first polling question for the audience, I'm curious to know what initial dose of melatonin is typically initiated at your institution.  I've listed a few doses, but if your dose is not one of the ones provided, please select other.  So, reviewing the answers, I see most participants have chosen 3 milligrams, which is what I  somewhat expected, because based on what I've seen in my institution in the available dosage hormone formulary, I've seen doses ranging anywhere from 3 to 6 milligrams as a starting  melatonin dose. However, given that there is such low risk for toxicity, again, I'd feel comfortable starting at the upper end of that range, around 6 milligrams.  And for my last polling question for the audience today, based on the results of this trial, would you recommend using melatonin for ICU delirium prophylaxis, yes or no?  So, the majority of the audience chose no. Purely based on the results, melatonin likely does not prevent ICU delirium. But these results would not deter me from giving melatonin  to patients if the team or the patient asked for it.  So, that concludes my presentation, and I thank you all for your participation. I'd be happy to answer any questions at this time. Hello, Jessica. The first question is,  what does the pre-deliric score consist of?  Yeah, great question. So, the pre-deliric score is actually a validated scoring tool used in the ICU. It looks at risk factors for delirium  based on the first 24 hours of a patient's ICU admission to determine whether patients are at high or low risk of developing delirium.  So, a couple of risk factors are incorporated, or predictors that are incorporated into the pre-deliric score would be patient's age,  APACHE-2 score, coma, the type of admission status, whether it was a planned ICU admission or not, the type of admission they had, whether it be a surgical, medical, trauma reason,  infection status, sedative use, and metabolic acidosis.  The tricky thing about the pre-deliric score is that this is a static model, so it doesn't account for any improvements or deterioration in health,  but rather the change in the probability of delirium development. So, it does really give you only a snapshot of the patient's risk of delirium when the delirium score,  the pre-deliric score was performed.  But it does give us a sense of whether or not patients are at high or low risk of developing delirium.  Okay, and then our next question is, how do you account for the variability in concentrations of melatonin products?  Would remeltion be more consistent?  So, there have been really limited trials looking at remeltion as well. Most of the data is used for,  that is, looking at isugilerium prophylaxis is for melatonin.  There are studies that have looked at melatonin 10 milligram doses, like I stated in the beginning, that showed supraphysiological levels.  This is a non-extended release formulation of that drug that was assessed. And so, it still does provide  physiological effects in the body. I would say I would have to look into remeltion data just a little bit more, but that is not primarily or regularly used  at our institution, nor is it on our formulary. So, it'd be hard for me to discuss its effects.  And one last question. Do you think CAM-ICU is the best method for validating delirium, or answering this question in this trial?  Yeah, so CAM-ICU is one of our validated scoring tools for assessing for delirium. There are other scoring tools that are utilized,  such as the Intensive Care Delirium Screening Checklist, or ICDS-C, that is another validated scoring tool. I think that CAM-ICU is definitely a valid scoring tool to utilize.  It does rely on the nursing staff, or the clinical staff to be familiar with the different components of measurements. And so, the fact that most nurses or clinical staff  were unfamiliar with this tool, makes me really question what was the standard at these participating sites? Whether they did use the ICDS-C scoring tool or something else.  So, it is interesting to know.  And that concludes our Q&A session. Thank you, Jessica Hu.  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 support of this Spotlight on Pharmacy webcast. How many attendees are you viewing this webinar with?  Now, I'd like to introduce our second presenter, Lydia Wehr. Hello, everyone. My name is Lydia Wehr, and I'm a current PGY-2 Critical Care Pharmacy resident at Brigham  and Women's Hospital. Thank you all for joining my presentation today on the article, Automate vs. Ketamine for Emergency Endotracheal Intubation, a Randomized Clinical Trial.  Rapid-sequence intubation is a technique that produces both fast and effective means of controlling an emergency airway through use of both an induction agent and neuromuscular  blocking agent. Our induction agents of choice include propofol, automata, and ketamine, but each do have various concerns with use.  And for completeness purposes, midazolam can also be used as an induction agent, but it's not commonly used due to the longer onset of action, which would prolong the time to  secure the airway. And lastly, the neuromuscular blocking agents commonly used are rocuronium and succinylcholine.  The KETOFED study was one of the first studies to look at the differences in outcomes following rapid-sequence intubation with automata as compared to ketamine.  The primary endpoint was the maximum SOFA score during the first three days in the intensive  care unit, with key secondary endpoints comparing the differences in the maximum and minimum SOFA scores recorded for those patients in that time frame, as well as 28-day all-cause  mortality. There were overall 469 patients enrolled, and no difference was found between the two  groups for the primary outcome of mean maximum SOFA scores, and no differences were noted in the secondary outcomes or in the immediate hemodynamic effects of the chosen agent.  Ultimately, the authors concluded that ketamine is a safe and effective alternative to automata as an induction agent for rapid-sequence intubation.  Next, a prospective assessment of data on emergency intubation from institutions in the National Emergency Airway Registry was conducted.  This assessment included patients who are at least 14 years old who underwent rapid-sequence intubation in the emergency department, again, with either ketamine or intaminate as the  induction agent. The primary outcome in this assessment was the incidence of peri-intubation hypertension, defined as a new systolic blood pressure less than 100.  Secondary outcomes included incidence of treatment for peri-intubation hypertension, as well as mortality.  The authors did find a statistically significant difference in the rates of peri-intubation hypertension, with ketamine ultimately leading to more hypertension, and they found that  more patients in the ketamine group also required treatment for this hypertension in the peri-intubation period, but they did not find any differences in mortality rates.  So, this assessment did contradict the results of the previous KETO-SED trial and found that ketamine may not be as safe when used as an induction agent as previously thought.  So, our first polling question for the presentation is, what is your preferred induction agent for rapid-sequence intubation? Our choices here are intaminate, ketamine, or propofol.  Great. So the majority of people did pick Atomidate. That is sort of what I was expecting given my short time practicing as a pharmacist. I've mostly seen Atomidate used for rapid  sequence intubation.  So moving on to the article itself, the study objective of the article was to compare clinical  outcomes between critically ill adult patients who received either Atomidate or Ketamine for rapid sequence intubation. And the authors did hypothesize that Ketamine would result  in an increased chance of survival at day seven after intubation.  So this was a prospective randomized parallel assignment open label trial that was conducted between 6-2016 and September 7, 2020 at an academic level one trauma center in Dallas,  Texas. There was a procedure focused airway team at the institution that responded to and  performed all of the intubations. And this team was staffed by the Department of Anesthesiology  and included at least two or more skilled operators with advanced intubation techniques and what appeared to be plenty of equipment available to them. And the patients who were  enrolled in the trial were randomized in a one-to-one fashion to either Atomidate dose at a range of 0.2 to 0.3 mgs per kilo or Ketamine dose at a range of one to two mgs.  Patients were included if they were at least 18 years old and were in need of emergency endotracheal intubation. Patients were excluded if they were less than 18 years old.  Women who were known to be pregnant at the time of intubation were excluded.  If patients were excluded, if they were also previously enrolled in the trial, if they required intubation without a sedative medication, such as in the case of cardiac arrest,  if they were allergic to Atomidate or Ketamine, or if they were wearing an opt-out bracelet indicating that they had officially opted out from trial participation. And lastly,  the airway team could specifically screen out a patient if they thought that one induction agent was indicated over the other given the clinical situation.  The primary endpoint of the study was the proportion survived on day seven after randomization. Secondary endpoints included proportions survived on day 28, duration of  mechanical ventilation, ICU length of stay, incidence of use, and duration of use of vasopressors, differences in SOFA scores on days one through four after randomization,  and assessment of a new diagnosis of adrenal insufficiency. And this new diagnosis could be made either clinically without the assessment of cortisol levels or in the  setting of laboratory assessments. Key exploratory endpoints included the immediate hemodynamic and  technical outcomes of intubation, and specifically the incidence of post-induction cardiovascular  collapse according to the Vanderbilt definition. And this was defined as a new systolic blood  pressure less than 65, the immediate need for a vasopressor bolus or dose escalation if the patient was already on a vasopressor, or cardiac arrest or death within one hour.  A minimum sample size of 750 was calculated using an 80% power and an alpha of 0.05 to detect a 10% difference in proportion survived at day seven. This calculation was also based  on previous quality improvement data that the institution had, which estimated survival rates  of 60% and 70% for automatate and ketamine respectively at that seven-day mark. The data was analyzed in an intention to treat manner, and a log-ranked chi-square test was used for  the assessment of primary outcomes. And secondary and exploratory endpoints were analyzed using chi-square tests, Fisher's exact tests, student's t-tests, and log-ranked tests,  depending on the type of data. So overall, there were 396 patients in the automatate arm and 395  in the ketamine arm. These patients had a median age of about 56 years old, were primarily male, and had an average weight of 84 kilos. The groups were well-matched at baseline,  and the authors noted that there were no statistically significant differences between  the groups. And of note, there were no variations in terms of hemodynamic status at baseline between  the two groups. However, just in assessing the baseline characteristics myself, I did note some few differences. So first, there were more patients in the automatate group who were  admitted to the surgical ICU and more admitted to the medical ICU who were in the ketamine arm.  Next, the NOS chronic health status score is used to describe baseline health status of patients enrolled in studies. And as you can see here, there were a higher number of patients  in the automatate group who fell into Category A compared to the ketamine arm who had more  patients fall into Categories B and D. And this just kind of indicates that the patients in the  automatate arm were likely slightly healthier at baseline with less functional limitations.  Additionally, there were slightly higher rates of shock being the reason for intubation in the automatate group and more rates of acute respiratory failure being the reason for  intubation in the ketamine group. But unfortunately, the shock was not further divided into what type of shock these patients were presenting with. However, given the rates  of diagnoses of sepsis in the pre-randomization and post-randomization period, it's likely that  most of them were presenting with septic shock. In terms of results, we can see that our primary  outcome of the proportion of survival at Day 7 was higher with ketamine at 85.1% compared to 77.3%  in the automatate group. And this difference was found to be statistically significant with a  hazard ratio of 1.6. One of the secondary outcomes was proportion survived at Day 28, which was found  to be 64.1% with automatate and 66.8% with ketamine. And this was not found to be statistically  significant. In terms of secondary outcomes, there were no statistically significant differences  found with any of these outcomes. The serious SOFA scores were actually reported in the  supplemental materials. But as you can see here, there were no differences between the two groups  with either of these. In terms of the exploratory outcomes, the majority did not yield a statistically  significant difference, but there was a clinically significant trend toward ketamine causing more  hemodynamic instability after induction. And this is just evidenced by a larger drop in blood  pressure and a greater increase in heart rate. There were also higher rates of IV vasopressor  bolus use, IV fluid bolus use, and CPR after induction with ketamine. And overall, there was  a statistically significant difference found in the rates of vasopressor utilization and the rates  of cardiovascular collapse according to the Vanderbilt definition with ketamine as compared  to automatate. So the authors of this study concluded that ketamine resulted in a reduction  in mortality at seven days after administration compared to automate, but that this difference was  not seen at the 28-day mark. So our second polling question is, have you ever seen peri-intubation hypertension as a result of ketamine administration for induction? Yes or no?  All right, so our answers here are pretty close. 59% of the audience chose no and 41% said yes. I personally have not seen a periant patient hypertension  from ketamine administration for rapid sequence intubation, but I think these results are somewhat interesting.  All right, so moving on to the discussion of the study. In terms of the patients included, I do think the authors used appropriate inclusion  and exclusion criteria to basically maximize the patients included in the assessment and more closely resemble the patient populations we may encounter  who would need emergency intubation. There were very minimal differences at baseline and the authors did note that there weren't any statistically significant differences.  Regardless of this, there was specifically one baseline characteristic that I would have liked to see and this is specifically the Apache scores of these patients.  The authors did report the NOS chronic health status score, but this is more of an indicator of chronic health rather than a marker of their acute illness.  And just because these patients were all admitted to the ICU after intubation and the primary outcome was further out from the study intervention,  I think it would be interesting to see what their Apache scores were at baseline to see if this would have any effect on the primary outcome.  In terms of dosing, I think the dosing used for the two induction agents were adequate and the reported median doses of 0.2 mg per kilo  and 1.2 mg per kilo for accommodate and ketamine respectively were both at the lower end of the range used in the study. And lastly, given the intubations were performed  by a highly trained procedure focused airway team that was part of the Department of Anesthesiology and responded to the intubations with multiple highly trained providers  and what appeared to be an abundance of equipment needed to manage these patients in the post intubation period, thought the study may just lack some generalizability  as it's possible not all institutions will have this highly trained team available to them to perform the intubations. In terms of endpoints and statistics,  I thought the primary outcome itself was likely to not be entirely representative of the effects of the induction agent they used during the intubation.  As these patients were admitted to the ICU after being intubated and received seven days of care before assessing the primary outcome, it does leave quite a bit of wiggle room  for multiple confounders to affect the primary outcome. I do think that assessing mortality is something that does need to be done, but that mortality rates at a shorter time point  such as 24 hours would likely be more representative of the effects of the chosen induction agent. The open label manner in which the study was conducted  also allowed the primary ICU teams to know which induction agents the patients received and could have led to some bias given the study was conducted  with the basis that the institution had previous quality improvement data that suggested ketamine would result in lower mortality rates compared to etomidate.  And this may have also led toward a clinically significant trend of the patients in the etomidate group having a higher likelihood of receiving a new diagnosis  of adrenal insufficiency compared to those in the ketamine arms. I do think it would have been better if the primary teams caring for these patients in the intensive care units  had been blinded to the agent they received and have the advanced airway team be privy to the information given they were the ones performing the intubations.  And lastly, some of the exploratory outcomes with regards to changes in hemodynamic effects were a little unclear. The Vanderbilt definition of cardiovascular collapse  was actually quite clear as it gave us very specific definitions, but the other exploratory outcomes such as the differences in pre and post-induction blood pressures  and heart rates were a bit more unclear in terms of the timing as it was not specified at what time point after intubation these hemodynamic measurements  had to be taken for comparison purposes.  So when comparing these results to the previously reported data, we can see that the results of our current study do kind of contradict the findings from the KETO-SED trial.  This is because the KETO-SED trial did not find any hemodynamic compromise after induction with ketamine, which our current study did. Additionally, the KETO-SED trial  found slight variations in SILFA scores following induction with either ketamine or etomidate and favored ketamine, but the current assessment found no differences  in the serial SILFA scores for four days following intubation. I didn't find these results were consistent with the prospective analysis  conducted with the near registry data though, because that study did find hemodynamic compromise after induction with ketamine, which our current study also did  in the exploratory outcomes. However, the near registry data did not show a mortality difference, which was actually noted with our current study.  So overall, my conclusion of this assessment is that while ketamine was shown to have a survival benefit at seven days in comparison to etomidate,  this result may not actually be indicative of the direct effects of the induction agents used. I do think that based on the results, specifically the exploratory outcome results,  that caution should be taken when using ketamine in patients with a tenuous hemodynamic status, just to prevent any further cardiovascular compromise after induction.  And with that, I'd like to thank you all for listening to my presentation, and I'm open to taking any questions at this time.  Our first question is, since the median dose of etomidate and ketamine used was at the lower end of the range, do you think that higher doses would have made a change  in the outcomes of the study?  I do think it's possible that higher doses would potentially lead to alterations in the possibly more in terms of the exploratory outcomes of the hemodynamic effects.  I couldn't say for certain whether they would have any effects on the primary outcome, again, given that the primary outcome was the proportion of patients survived at day seven.  So that, again, leaves a lot of wiggle room for a lot of confounders to affect the primary outcome. But I think that giving higher doses of these induction agents  could certainly cause more alterations in their hemodynamic status. Specifically, as we saw alterations with ketamine, specifically giving a higher dose of ketamine for induction,  it's quite possible that it could lead to even more cardiovascular collapse.  And our next question is, did the authors investigate other adverse effects,  such as delirium or emergent reactions, emergence reactions?  Actually, no, they did not assess those as outcomes. I hadn't thought about that, but that would be quite interesting to see if there were any differences,  specifically noting the emergence reactions with ketamine.  Okay, thank you. That concludes our Q&A session. Thank you, Lydia Ware.  Now I'd like to introduce our final presenter, Alyssa Lear.  Hi, everyone. My name is Alyssa Lear, and I am currently one of the PGY-2 Critical Care Residents at the Medical University of South Carolina.  And today I'll be presenting on intravenous morinone for cerebral vasospasm and subarachnoid hemorrhage, also known as the Milriss spasm study.  To begin, narrowing of the cerebral arteries or vasospasm  after aneurysmal subarachnoid hemorrhage is a contributor for poor outcomes. These cerebral vasospasms occur approximately three to four days after aneurysm rupture  and can last for a few weeks, but generally resolves within 21 days. Delayed cerebral ischemia also develops in about one third of patients after aneurysmal subarachnoid hemorrhage.  And despite a general belief that vasospasm causes delayed cerebral ischemia, you can actually have vasospasms without DCI and you can have DCI without vasospasms.  However, delayed cerebral ischemia can develop in fewer than like one half of patients with vasospasms.  Guideline recommendations for patients with aneurysmal subarachnoid hemorrhages include induced systemic hypertension, maintaining uvulemia, endovascular angioplasty,  intraarterial vasodilator therapies, and the use of namodipine.  Milrinone is a phosphodiesterase-3 inhibitor with cerebral vasodilatory properties. And there are some case theories utilizing it  for cerebral vasospasms after subarachnoid hemorrhages, particularly a study by Frannicelli and colleagues used intraarterial milrinone, and they were actually able to show  an increase in vessel diameter after use of it. However, it's still unknown if IV milrinone could decrease delayed cerebral ischemia, withhold endovascular angioplasty procedures,  or improve functional outcomes.  And that leads me to the objective of this study, which is to compare patients receiving both IV milrinone and induced hypertension versus just induced hypertension alone.  This study looked at patients' six-month functional disabilities, which they defined as a score of two to six  in the modified Rankin scale, vasospasm-related brain infarctions on imaging studies, the rate of endovascular angioplasty for vasospasms,  and also IV milrinone tolerance and adverse effects.  This was a observational study utilizing both prospective and retrospective data at Nantes University Hospital in France. They included patients treated for vasospasms  following aneurysmal subarachnoid hemorrhage, and the IV milrinone group consisted of patients from June 2018 to January 2020, and the control group was included  from April to December 2014.  The 2014 timeframe for the control group was chosen because this institution intermittently used milrinone for vasospasms since 2015,  but officially developed a strict protocol in 2017.  Additionally, patients were excluded from this study if they were pregnant less than or equal to 18 years, had a vasospasm unrelated to an aneurysmal subarachnoid hemorrhage,  were under guardianship, or had no French health insurance.  Identification of vasospasm in this study was determined with clinical examination in daily transcranial color-coded duplex dopplers of the middle cerebral arteries.  The gold standard of vasospasm detection for most institutions relies on a change in a patient's neuro exam from baseline, and TCDs are typically utilized  to compare flow velocities in the larger vessels.  Vasospasm in this study was further diagnosed using CT angiography and was able to be characterized as either mild, moderate, or severe. The study did characterize the stenosis,  however, they did not state their criteria for angioplasty.  Both patients in this study, or both cohorts in this study, were treated in correlation with the guidelines and received nemotipine. However, patients in the control group  underwent induced hypertension, which they targeted a mean arterial blood pressure of 100 to 120 millimeters of mercury.  This induced hypertension was the same for both groups and consisted of maintaining eubulemia and stopping any antihypertensive medications  and also utilizing norepinephrine if needed. In the IV milrinone group, once they attained that MAP goal of 100 to 120, the IV milrinone was started about an hour after.  IV milrinone was initiated at 0.5 mics per kick per minute,  and it could be increased to a maximum of 1.5 mics per kick per minute. I just wanna point out that this dose is a lot larger than a cardiac indication.  If a MAP was below that 100,  their norepinephrine dose could be increased to 1.5 mics per kick per minute. However, if patients in the IV milrinone group were still not attaining that MAP goal,  then their dose was reduced of milrinone to 0.5 mics per kick per minute. And if that goal was still not achieved, then they were willing to turn off the milrinone.  The study placed a high priority on the induced hypertension. And the study did not delineate exactly who or when they started the milrinone in patients,  and the weaning was left up to the intensivist, which I thought represented what we see in clinical practice. However, did not set a duration for how long milrinone had to be on.  Data for the IV milrinone group was collected prospectively, except for neurological outcomes as these were extracted from patient charts. This relies on good documentation  and could be at risk for bias considering the patient was not blinded to the group assignment. However, radiological images were assessed  by a neuroradiologist who was blinded to the assignment.  The outcomes of this study included the incidence of functional disability and vasospasms related brain infarctions at six months. They also looked at first line  and rescue use of endovascular angioplasty and features of poor tolerance of treatment for vasospasms.  Descriptive and appropriate statistical analysis were chosen based on categorical or continuous variables. And a P-value of less than 0.05 was also considered significant.  So to go over some of the results of this study, there was about 190 patients screened for both groups. Many patients were excluded  for not having aneurysmal subarachnoid hemorrhages, no vasospasms to treat or no health insurance or pregnancy. And that left 41 patients in the IV milrinone group  and 53 patients in the control group.  Baseline characteristics were similar between both groups and not statistically significant. However, a low grade subarachnoid hemorrhage,  which could be defined as a world federation of neurosurgical societies, grade one or two, was more common in the IV milrinone group compared to the control group.  Additionally, a high grade subarachnoid hemorrhage, which could be defined as a WFNS score of five was more common in the control group. And this could have led intensivists  to rely more on angiograms more often to identify vasospasms as patients who have a WFNS score of five would have a poor baseline neuroexamination. Also, the higher the WFNS score,  the worse prognosis it is for patients with subarachnoid hemorrhages. So that could skew some functional results that could be seen in the end as well.  And patients' quality of life or functional status might not be as strong as somebody who has a WFNS score of one or two.  The time from aneurysm rupture to vasospasm was about seven days in both groups, and that is consistent to what is seen in the literature. And however, I just want to point out  that vasospasms were actually a little more severe in the IV milrinone group.  Additionally, the median duration of IV milrinone in the study for both groups was about five days. However, the average duration of milrinone was about five days.  However, milrinone did have to be discontinued prematurely in about 29% of the patients due to poor tolerance. In the supplemental, it did state that eight patients  had to discontinue milrinone within one day. However, the study did not really characterize the amount of time that the milrinone was on for these patients.  And if it was only on for a few hours, it's kind of hard to contribute functional outcomes to a medication that was only working for a few hours.  Additionally, when IV milrinone was started in patients, it induced a decrease in their blood pressure and norepinephrine doses had to be increased.  And looking at the graph over here, the median dose of norepinephrine used in the induced hypertension group was about 0.5 mcg per minute.  And you can see when IV milrinone was used, the norepinephrine doses were increased to about one mcg per minute. So you could also question that some of the side effects  noted in this study, whether they were from milrinone or norepinephrine itself.  The rate of endovascular angioplasty was lower in the IV milrinone group.  And I want to comment on the ischemic sequelae on the CT scan at six months. I just want to highlight again that you can have DCI without vasospasms  and you can have vasospasms without DCI. However, this study did contribute all ischemic sequelae that is seen on the CT scan to the vasospasms.  I want to point out that the control group about 34% is actually consistent to the statistics seen in the literature, where about one half or one third of patients  developed DCI after vasospasms.  And the 10% in the IV milrinone group could be a little low, which could be indicative of differences in the baseline characteristics between these two groups.  And importantly, IV milrinone was actually,  had better functional outcome compared to the control group.  And mortality was actually low in both groups in this study. And that could just, that's interesting, like I said before, with the control group  who had more higher grade subarachnoid hemorrhages at baseline.  Additionally, safety outcomes were reported from IV milrinone and arrhythmias were similar between both groups. However, hyponatremia and hypokalemia  was seen a little bit more in the IV milrinone group compared to the control group.  Overall from the study, milrinone was prematurely discontinued due to poor tolerance in 29% of patients. However, IV milrinone was associated  with a lower rate of endovascular angioplasty and a lower likelihood of six month functional disability and vasospasm related brain infarction.  Some strengths of the study is it reported both clinical and safety outcomes. And it was one of the first controlled studies assessing IV milrinone  as treatment for cerebral vasospasms. And they also assessed some long-term outcomes using the modified Rankin score as well.  I wanted to highlight some limitations of the study. This is a single center observational before and after study design. Being single center,  it can limit the generalizability of this study. And then I want to note the difference in the time periods. They utilize 2014 versus 2018 to 2020.  Neurocritical care is an ever evolving area of critical care and there definitely could have been different treatment algorithms between those two time periods.  I also think it would have been important to know the trigger for angiograms between the two groups too in time periods as well. Just like I mentioned previously,  with a higher WFNS score in the control group, they might have had to rely on angiograms more frequently in order to diagnose vasospasms.  Additionally, guidelines recommend induced hypertension and they did follow that within this study. However, I just want to mention that the optimal blood pressure is still unknown  for which to target in patients with aneurysmal subarachnoid hemorrhages.  And also talking about milrinone doses, the optimal dose and duration of milrinone itself is unknown for cerebral vasospasms after aneurysmal subarachnoid hemorrhages as well.  There is variable dosing across studies utilizing anywhere from 0.5 mics per tick per minute to 2.5 mics per tick per minute, which are a lot larger than our cardiac indications  as previously mentioned.  And then patients in the study could also undergo endovascular angioplasty. So it's hard to say that all the six-month functional outcomes  were largely related to IV milrinone alone.  Additionally, many patients may not be able to tolerate the use of milrinone, especially at those high doses.  And this study did have 29% of patients prematurely discontinue it. So I also would have liked to know the timeframe that the medication was able to actually be on  and how long they were able to tolerate it.  As previously mentioned too, a non-blinded investigator identified neurological outcomes and completed chart review, and that leads to a risk of bias.  And the study defined a dose of norepinephrine greater than or equal to 1.5 mics per tick per minute as the point to decrease or withhold milrinone.  This was an arbitrary number set by this study,  and for investigators, however, that is a pretty big dose of norepinephrine. And I also want to note that it might seem to be counterintuitive  to do both norepinephrine and milrinone together. But with that being said, it's still really unknown the clear picture of how either affects CNS vasculature,  and there is thought to be a receptor distribution within the CNS. So I think in the end, we need to really understand the physiology  of subarachnoid hemorrhages and vasospasms more clearly in order to better direct treatment in general too.  The study also decided that all cerebral infarctions were secondary to vasospasms, and then no cost savings of milrinone was identified, which could be interesting to see  if milrinone has a cost savings effect too.  Overall, my takeaway points from this study is that we still need some more perspective randomized studies utilizing milrinone for cerebral vasospasms  after aneurysmal subarachnoid hemorrhages. IV milrinone offers cerebral vasodilatory properties. However, you have to take into consideration its adverse effects,  and if patients will even tolerate the use of milrinone. And lastly, IV milrinone in this study was associated with a lower rate of endovascular angioplasty  and has some positive long-term neurological and radio outcomes in this study as well.  I'd like to thank... Oh, now it brings me to my polling question. Do you use IV milrinone at your institutions for vasospasms after aneurysmal subarachnoid hemorrhages?  I think this is an interesting response. I feel like some institutions might utilize it in certain refractory cases or in patients  that they know might tolerate this dose, but I think that this still has limited data, so I'm not surprised by most people saying no to this answer, or to this question.  And my last polling question is, if you use ivimorinone, what dosing range of ivimorinone  do you utilize at your institution for vasospasms after aneurysmal subarachnoid hemorrhages?  Yes, I was expecting most people after this study to probably choose the first answer as this is the first controlled study that did look at the dose of 0.5 mics per kick  per minute to 1.5 mics per kick per minute. And I'd like to thank SDCM for this opportunity to present and thank you all for listening. I will take any questions at this time.  The first question is, did the authors reduce milrinone for patients with renal dysfunction at any point? Yeah, that's a good question.  They actually did not state any baseline characteristics of renal function, which is something I would have liked to see in this study.  They did look at adverse effects of milrinone and what they actually saw was that milrinone increased urine output and that's what they reported based on renal function.  However, I would have liked to see more of who was the right candidate to start this medication in.  Did they take renal dysfunction into consideration and did they ever dose reduce based on that, which the study did not actually delineate.  Thank you, and that concludes our Q&A session. Thank you, Alyssa Lear. Thank you.  And thank you to our presenters today and all of the audience for attending. Please join us on the third Friday of the month from 2 to 3 p.m. Eastern  Standard Time for the next Journal Club Spotlight on Pharmacy. That concludes our presentation today.

Video Summary

Hello and welcome to today's Journal Club Spotlight on Pharmacy webcast. This webcast focuses on three different studies. The first study looks at prophylactic melatonin for delirium in the intensive care unit. The second study compares atomidate and ketamine for emergency endotracheal intubation. And the third study examines intravenous milrinone for cerebral vasospasm in subarachnoid hemorrhage. Each study presents its objectives, methods, results, and conclusions. The first study found no statistically significant difference in delirium rates between patients receiving melatonin and those receiving a placebo. The second study found that ketamine resulted in a reduction in mortality at seven days compared to atomidate. The third study found that IV milrinone was associated with a lower rate of endovascular angioplasty and had some positive long-term neurological outcomes. Each presenter also discussed the strengths and limitations of their respective studies. Overall, these studies provide valuable insights into the use of melatonin, ketamine, and milrinone in critical care settings. However, further research is needed to fully evaluate the efficacy and safety of these interventions.

Asset Subtitle

Pharmacology, 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.

Jessica Hu, PharmD
Wibrow B, Martinez FE, Myers E, et al. Prophylactic melatonin for delirium in intensive care (Pro-MEDIC): a randomized controlled trial. Intensive Care Med. 2022;48:414-425).

Lydia Ware, PharmD
Matchett G, Gasanova I, Riccio CA, et al. Etomidate versus ketamine for emergency endotracheal intubation: a randomized clinical trial. Intensive Care Med. 2022 Jan;48(1):78-91.

Alyssa Lear, PharmD
Lakhal K, Hivert A, Alexandre PL, et al. Intravenous milrinone for cerebral vasospasm in subarachnoid hemorrhage: the MILRISPASM controlled before-after study. Neurocrit Care. 2021 Dec;35(3):669-679.

Follow the conversation at #SCCMCPPJC."

Meta Tag

Content Type Webcast

Knowledge Area Pharmacology

Knowledge Area Neuroscience

Knowledge Level Intermediate

Knowledge Level Advanced

Membership Level Professional

Membership Level Select

Tag Analgesia and Sedation

Tag Delirium

Tag Subarachnoid Hemorrhage

Year 2022

Keywords

Pharmacy webcast

prophylactic melatonin

delirium

atomidate

ketamine

emergency endotracheal intubation

intravenous milrinone

cerebral vasospasm

subarachnoid hemorrhage

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