My name is Bridget Crum, I'm a Clinical Pharmacist in the Medical Intensive Care Unit at Duke University Hospital. I'm the Residency Program Director for our PGY2 Critical Care Pharmacy Residency Program and an Assistant Professor of Clinical Education for UNC Eshelman School of Pharmacy. Thank you for joining me as I discuss the contributions of women pharmacists to critical care practice by reviewing literature published in 2021. I have no relevant financial disclosures to report. My objectives mirror those of my colleagues on this panel, though I will focus specifically on the contributions of women pharmacists to the critical care literature. For my methodology, I used a similar approach to that of Dr. Igneri in last year's panel. The Clinical Pharmacy and Pharmacology section of SCCM has a research subcommittee with many important charges. One of those charges is the monthly publication of the CPP Pharmacotherapy Literature Update. This group of pharmacists reviews the table of contents of more than 40 medical journals and selects key articles pertaining to the pharmacotherapeutics of critically ill patients. Of this review, I was able to identify 10 articles in which the primary author was a woman pharmacist. Working to gather additional potential articles to discuss today, I went back and reviewed manually seven pharmacy-based journals and critical care journals that are historically pharmacy-friendly. I identified an additional 39 articles where women pharmacists were primary authors and 10 articles where the senior author was a woman pharmacist. To pare down these articles, I focused my selection on women pharmacists who are primary authors. I further categorized these abstracts into eight buckets and have selected one to three articles and six of these eight categories to discuss today. We'll start first with administration. I categorized several types of articles as administrative, including mentorship, teaching, major publication reviews, productivity metrics, and operations. Amy Shaw and colleagues published their early experience with pump relocation for isolated COVID patients and the administration of medications by extension tubing. This single-century retrospective pre-post study evaluated the same 18 patients pre-implementation and post-implementation of pump relocation to outside of the patient care rooms. All patients required both contact and special droplet isolation procedures and received standardized infection risk bundles for CLABSI prevention. The medications relocated outside of patient rooms included vasopressors or inotropes, analgesics, sedatives, insulin, heparin, and neuromuscular blocking agents. In the cohort, 85% were mechanically ventilated. The primary endpoint of this study was nursing room entry. Retrospectively, that can be pretty challenging, so the group used objective documentation in the medical record that included turns, proning, patient assessments, IV piggyback bag and rate changes, ventilator setting changes, finger sticks, and APTT draws. Other labs and medication administration were not counted since they were expected to be the same in both groups. The same procedure was used post-pump relocation except that IV piggyback bag and rate changes were excluded since these now occurred outside of the patient room. The mean number of entries following pump relocation was significantly lower in the post-pump relocation group. For safety endpoints, hyperglycemia, defined as a blood sugar greater than 300, and hypotension, defined as a systolic less than 90, and bloodstream infection during ICU stay were not different between groups. No patients experienced an extravasation event or a CLABSI. Although a small study, I found the information practical, a proof of concept, and easily translatable into practice during the pandemic when we were constantly evaluating PPE preservation opportunities. Pharmacists love a good anticoagulation reversal study. Ava Cascone and colleagues in a multicenter retrospective cohort across a single health system in Texas evaluated four-factor PCC for reversal of factor Xa inhibitors in the setting of either traumatic or spontaneous intracranial hemorrhage. Traumatic patients received either 25 units per kilo or 50 units per kilo. The primary endpoint was hemostatic efficacy, which was defined as hematoma volume with no change, less than or equal to 35% change, or improvement on follow-up imaging. There is no difference in hemostatic efficacy between patients who receive low dose as compared to standard dose four-factor PCC in this study. Thrombotic events defined as stroke or TIA, DVT, MI, or PE were also not different between groups. Claire McMahan and colleagues similarly assessed PCC dosing in a single center retrospective pre-post study of 226 patients with a bleeding event receiving warfarin. These events were characterized as a CNS bleed, a non-CNS bleed with an INR of less than or equal to 6, or non-CNS bleeds with an INR of greater than 6. Two dosing strategies were evaluated, a weight-based compared to fixed dose strategy. In the weight-based strategy, all patients with a CNS bleed received the same weight-based dose per package insert regardless of INR, whereas non-CNS dosing was based on weight and INR. In the fixed dose group, if a patient had a CNS bleed or a non-CNS bleed with an INR greater than 6, 2,000 units were administered. All other indications for four-factor PCC received 1,000 units. The primary endpoint was INR target attainment. For patients with a CNS bleed, achievement of an INR of less than 1.4 occurred similarly between groups. It's important to note that the median dose administered in the weight-based group was 2,100 units, which was pretty similar to the fixed dose strategy. In non-CNS bleeds with an INR of less than or equal to 6, a weight-based dosing strategy was more likely to achieve an INR of less than or equal to 1.5 compared to fixed dose. The weight-based group received about twice the fixed dose group. For non-CNS bleeds with an INR of greater than 6, target attainment was similar between groups, but there were only 19 patients evaluated in this cohort. The incidence of thrombotic events was not reported in this study. And to conclude, a fixed dose strategy of 2,000 units seems to be reasonable for patients with a CNS bleed, though a fixed dose strategy of 1,000 units for other indications really needs to be further evaluated. We're going to switch gears from anticoagulation to infectious diseases. As I'm sure many of you are aware, there's movement away from trough-based dosing of vancomycin to an AUC-based approach, or area under the curve. Troughs of 15 to 20 have historically been used for simplicity as a surrogate target for vancomycin exposure, or AUC, but trough concentrations are poor predictors of overall drug exposure, and higher troughs are associated with a higher risk of nephrotoxicity without improvement in efficacy. Strategies to predict AUC can be done using two-point kinetics, or drawing a peak and a trough, but from a resource standpoint, that's less than desirable when considering the frequency and timing of blood draws in lab utilization. Bayesian software has been used to predict the AUC from population-based pharmacokinetics to estimate individual drug exposure. Prior to the publication of the study we're about to discuss, evaluations of Bayesian software models in critically ill adults had been limited to fewer than 100 patients, and these studies reported low bias with variable precision. Sujita Narayan and colleagues evaluated three Bayesian software programs in a single-center retrospective cohort of 330 patients in 466 levels. This study was conducted in a 54-bed Australian ICU. 44% of admissions were surgical, 70% of patients were receiving vasopressors, and the average Apache 3 score was 62. It's important to note that patients requiring renal replacement therapy were excluded from this study. To understand the results of this study, it's important to understand the concepts of bias and precision. Bias is the difference between observed and predicted levels. A model with low bias shows a large difference between the observed and predicted levels. This means that the model is overall poor. Precision is reported as the standard deviation, the root-mean-square error, and limits of agreement. A model with low precision means that the predicted value may occur to a similar extent both above and below the observed value, and that would be bad because you couldn't adjust your dose in one direction or another to account for it. All three models evaluated in this study demonstrated both low bias and low precision, as you can see in these bland altmet plots, where the y-axis is the difference between the predicted and observed trough concentration, and the x-axis is the vancomycin trough concentration. Interpreting the finding of low bias, you can see that the estimates fluctuate by an AUC of 100 to 150 around the observed value. A match between the observed and predicted concentrations for dose range categories was 60.9% for the Godey and colleagues model, 58.6% for the Thompson and colleagues model, and 50.9% for the Collin and colleagues model. So in other words, in approximately half of the cases, a dose change would be needed based on the predicted values, but not the observed values, and vice versa. The authors concluded that Bayesian pharmacokinetic models may perform poorly in critically ill adults, and that about half of our patients will require a dose change if these models are used to determine an initial dosing regimen. To be honest, though, this is probably pretty similar to what's observed with trough-based dosing. Variable renal function, extremes of body weights, resuscitation, and a number of other confounders make vancomycin dosing in critically ill adults often more of an art than a science. I'm confident that there's going to be more data on this topic published in the next couple of years. I'd like to say a kudos to the study team for such an interesting study, and for explaining a really challenging topic so well directly in the publication. Push dose vasopressors are always a hot topic at my institution. Most of the data supporting use is in the perioperative or periintubation period. This study by Jacqueline Hahn and colleagues evaluated push dose vasopressor utilization in septic shock and caught my eye immediately. In this multicenter retrospective propensity match study, patients were included if they received push dose phenylephrine within 60 minutes before or 120 minutes after the initiation of norepinephrine. Patients were assessed for hemodynamic stability, defined as a mean arterial pressure greater than or equal to 65, for six hours without the increase of a vasopressor. The study team assessed when the patient achieved hemodynamic stability by this definition, then calculated the time to hemodynamic stability as a continuous variable, and adjudicated if this time occurred within the first three hours after norepinephrine initiation, which was the primary endpoint, or within 12 hours, which was the secondary endpoint. Multivariate and logistic regression models were run with key covariates, including ICU location, mechanical ventilation, severity of illness scoring, liver failure, lactate, and a few others. The odds of hemodynamic stability at three hours were higher in the push dose vasopressor group, though this was not a sustained response out to 12 hours. In univariate analysis, patients who received push dose vasopressors had longer ICU length of stay and higher mortality. In their model, the odds of ICU mortality were higher in the push dose vasopressor group. The authors concluded that push dose vasopressors result in early but transient improvements in blood pressure, though there's a signal for harm. While this study did not evaluate dosing and administration errors, these have been well described in the emergency department literature. I think we should advocate for push dose vasopressors in the setting of periprocedural hypotension, or if a continuous infusion is not readily available, but otherwise they should be used very cautiously in patients with septic shock. Now we get to talk about sedation. Most modern sedation trials reinforce the merits of light sedation, which we know improves numerous clinical outcomes, but there are certainly cases where deep sedation is warranted to minimize patient ventilator interactions, which can lead to hypoxemia, ventilator-induced lung injury, or even self-induced lung injury. We've seen this with COVID ARDS, but deep sedation is well described long-term consequences that we need to minimize. We've long assumed that sedation suppresses respiratory effort, but in practice that has variable effects. Amy Zerba and colleagues designed this trial to assess the association of respiratory drive and depth of sedation in mechanically ventilated patients using airway occlusion pressure, or P100, which quantifies the motor output from the respiratory center at the beginning of inspiration when the airway is occluded for 100 milliseconds. Each included patient had a total of six measurements, which were taken prior to paired SATs and SBTs. Patients were excluded if they had neuromuscular disease with compromised respiratory function, obstructive airway disease, tracheostomy, or were receiving neuromuscular blocking agents at the time of the P100 assessment. Fifty-six patients were included with 197 airway occlusion pressure measurements. Included patients were primarily older males intubated for hypoxic respiratory failure. About half had ARDS, and the baseline airway occlusion pressure was 0.4 centimeters of water. At the time of enrollment, about half were receiving an opiate infusion, and propofol was the most commonly used sedative at a fairly robust rate of 45 mics per kilo per minute. The median RAS at time of inclusion was negative 4. Diving into the results, for all the non-pulmonologists listening, it's important to understand how to interpret them. The higher the airway occlusion pressure, the greater the patient's respiratory drive. Of the 197 evaluations, the median P100 was 0.1, with nearly half of the evaluations demonstrating no respiratory effort, about 19% of them demonstrating a P100 between 0.5 and 1.5 centimeters of water, and a quarter of the evaluations observed a high respiratory drive. In the box and whisker on the right, you can see that depth of sedation, as measured by RAS, and respiratory drive are poorly correlated. Deep sedation doesn't always lead to cessation of respiratory effort, and light sedation doesn't always preserve it. A patient is considered to have moderate respiratory drive when airway occlusion pressure reads between 0.2 and 1, and patients with an average moderate respiratory drive in this range had more ventilator-free days observed compared to those with a low or high occlusion pressure. The authors concluded that sedation depth doesn't reliably correlate with respiratory drive as measured by the airway occlusion pressure. Although the P100 does have some limitations as a measure of respiratory effort, I thought this study was novel, thought-provoking, and presents a potential bedside tool for clinicians. Seventeen articles met eligibility for inclusion into this presentation in the PATAS category, so choosing a select few was incredibly difficult. I created an honorable mentions list to give a shout-out to these amazing women pharmacists across the country and encourage them to continue this inspiring and practice-changing work. I'm sure all of those who are listening have used more neuromuscular blocking agents in the past two years cumulatively than in your previous experience, so like you all, I've been hungry for information to help me learn how to manage these patients better. These two studies led by Melissa Thompson-Baston from Kentucky and Julie DeBridge from Pittsburgh evaluated dosing strategies of cis-cetracurium in patients with moderate or severe ARDS. In each study, the fixed-dose group received 37.5 mg per hour that was used in both acurasis and ROSE. Thompson-Baston compared fixed-dose to titration of cis-cetracurium to a target train of four of one to two out of four twitches. DeBridge and colleagues compared fixed-dose to titration to ventilator synchrony, which was defined as cessation of respiratory effort or train of four base monitoring. As their primary endpoint, Thompson-Baston and colleagues evaluated the P to F ratio at three time points, at baseline, 24 hours, and 48 hours following cis-cetracurium initiation. P to F improved at all three time points but was not different between groups. Medical and operational endpoints like ventilator free days, reinitiation of cis-cetracurium, need for boluses, length of stay, and mortality were similar between groups. Notably, drug consumption was significantly lower in the train of four titrated arm. DeBridge and colleagues evaluated drug consumption, which was lower in the ventilator synchrony arm compared to both the train of four and fixed-dose group. P to F ratio and oxygenation index were not different from baseline to hours 12, 24, 36, and 48, as you can see in the box and whisker plots. Clinical endpoints, including length of stay, mortality, and ventilator time were also similar between groups. Also of interest pertaining to neuromuscular blocking agents was Laura Gertzinger's publication on the early experience of rocuronium infusions in critically ill patients. The study was very helpful for us as we were similarly dealing with cis-cetracurium shortage in 2021. In this cohort, rocuronium titration was not standardized. It was used as fixed-dose or titrated to either train of four or ventilator synchrony per provider preference. The median dose that patients received was seven mics per kilo per minute for a median duration of 27 hours. More than a third of the cohort had multi-organ failure, which offered an opportunity to evaluate neuromuscular recovery following discontinuation of rocuronium. Neuromuscular blocking recovery would be expected to be slower for patients who receive rocuronium with multi-organ failure because it's hepatically metabolized. As anticipated, patients with multi-organ failure were more likely to have a higher degree of neuromuscular blockade, as evidenced by a higher frequency of train of four zero to one, and a slower time to neuromuscular recovery, with a median time to recovery of 10 hours for patients with multi-organ failure compared to 4.6 hours in patients without. My takeaways from this publication are, first, to adjust my expectations with time to neuromuscular recovery in patients receiving rocuronium infusions, and second, that rocuronium infusions should probably be titrated down more aggressively due to its long half-life and higher degree of accumulation, particularly in patients with multi-organ failure. I also mused a little bit on the ethical implications if a patient is close to end of life and receiving a rocuronium infusion. Delay of withdrawal of support may be necessary to allow time to neuromuscular recovery. I think we can all agree that drug shortages stink, but with them, there's always a silver lining. We become more creative and resourceful and get to learn new things, and this publication is an excellent example of that. To wrap it up, women pharmacists continue to publish high-quality, translatable research across a spectrum of topics. We wear a number of professional hats, and research is largely completed within the context of all other patient care, teaching, and administrative responsibilities. Our drive to publish is often self-motivated, and few of us have protected time for research or receive reward or advancement for doing so. And departmental and institutional support for pharmacists in general to complete research is needed. I would also like to encourage all of the women listening to become more involved in the peer review process. We are largely underrepresented on journal editorial boards, as peer reviewers, and in publishing in general. Systematic changes that address these disparities are urgently needed. Thank you for joining me today in this recap of the contributions of women pharmacists to the critical care literature in 2021. Please do not hesitate to reach out to me with any questions.

Bridget Crum

Clinical Pharmacist

Residency Program Director

women pharmacists

critical care practice