Edoxaban pharmacokinetics during in vitro continuous renal replacement therapy.

BACKGROUND: To evaluate the clearance of edoxaban during modeled in vitro continuous renal replacement therapy (CRRT), assess protein binding and circuit adsorption, and provide initial dosing recommendations. METHODS: Edoxaban was added to the CRRT circuit and serial pre-filter bovine blood samples were collected along with post-filter blood and effluent samples. All experiments were performed in duplicate using continuous veno-venous hemofiltration (CVVH) and hemodialysis (CVVHD) modes, with varying filter types, flow rates, and point of CVVH replacement fluid dilution. Concentrations of edoxaban and urea were quantified via liquid chromatography-tandem mass spectrometry. Plasma pharmacokinetic parameters for edoxaban were estimated via noncompartmental analysis. Two and three-way analysis of variance (ANOVA) models were built to assess the effects of mode, filter type, flow rate, and point of dilution on CLCRRT. Linear regression was utilized to provide dosing estimations across CRRT effluent flow rates from 0.5 to 5 L/h. Optimal edoxaban doses were suggested using CLCRRT and population non-renal clearance (CLNR) to estimate total clearance and match the systemic AUC associated with efficacy in the treatment of venous thromboembolism. RESULTS: Edoxaban clearance from the CRRT circuit occurred primarily via hemofilter adsorption to the HF1400 and M150 filters at 74% and 65%, respectively, while mean percent protein binding was 41%. Multivariate analyses confirmed the lack of influence of CRRT mode, filter type, and point of dilution on the CLCRRT of edoxaban allowing dosing recommendations to be made based on effluent flow rate. Edoxaban doses of 30-45 mg once daily were estimated to achieve target the AUC threshold for flow rates from 0.5 to 5 L/h. CONCLUSION: For CRRT flow rates most employed in clinical practice, an edoxaban dose of 45 mg once daily is predicted to achieve target systemic exposure thresholds for venous thromboembolism treatment. The safety and efficacy of this proposed dosing warrants further investigation in clinical studies.

Efficacy and Safety of Perioperative Angiotensin II Versus Phenylephrine as a First-Line Continuous Infusion Vasopressor in Kidney Transplant Recipients.

INTRODUCTION: Angiotensin II (ATII) maintains blood pressure via RAAS with a beneficial adverse effect profile versus catecholamines and phenylephrine. Head-to-head data comparing ATII to phenylephrine are lacking regarding renal allograft function, hemodynamic efficacy, and safety within the perioperative period of kidney transplantation. METHODS: This single-center, retrospective study included adult kidney transplant recipients who received continuous infusions of ATII or phenylephrine within a 24-h perioperative period as a first-line vasopressor according to an institutional algorithm. The primary endpoint was allograft function. Secondary endpoints were hemodynamic efficacy and adverse effects. RESULTS: Among 105 patients, there was no significant difference in IGF (p = 0.545), SGF (p = 0.557), or DGF (p = 0.878) between patient cohorts. In the 34 patients with cold ischemia time (CIT) > 14-h, IGF was higher (p = 0.013) and DGF (p = 0.045) was lower in the ATII cohort versus phenylephrine. In all patients, ATII was associated with a decreased need for additional vasopressor agents (p < 0.001). Adverse effect profiles were similar between cohorts (p > 0.05). CONCLUSION: Among kidney transplant recipients, ATII may be a suitable first-line alternative compared with phenylephrine in the perioperative period for hypotension management with a reduced need for additional vasopressor support. Allograft benefits were observed in patients with prolonged CIT.

Angiotensin II as a Vasopressor for Perioperative Hypotension in Solid Organ Transplant.

During the perioperative period of transplantation, patients experience hypotension secondary to the side effects of anesthesia, surgical stress, inflammatory triggering, and intraoperative fluid shifts, among others causes. Vasopressor support, in this context, must reverse systemic hypotension, but ideally, the agents used should benefit allograft function and avoid the adverse events commonly seen after transplantation. Traditional therapies to reverse hypotension include catecholamine vasopressors (norepinephrine, epinephrine, dopamine, and phenylephrine), but their utility is limited when considering allograft complications and adverse events such as arrhythmias with agents with beta-adrenergic properties. Synthetic angiotensin II (AT2S-[Giapreza]) is a novel vasopressor indicated for distributive shock with a unique mechanism of action as an angiotensin receptor agonist restoring balance to an often-disrupted renin angiotensin aldosterone system. Additionally, AT2S provides a balanced afferent and efferent arteriole vasoconstriction at the level of the kidney and could avoid the arrhythmic complications of a beta-adrenergic agonist. While the data, to date, are limited, AT2S has demonstrated safety in case reports, pilot studies, and small series in the kidney, liver, heart, and lung transplant populations. There are physiologic and hemodynamic reasons why AT2S could be a more utilized agent in these populations, but further investigation is warranted.

Qualitative analysis of preparation and planning habits of students with low-performance on high-stakes practice examinations (pre-NAPLEX®).

OBJECTIVE: The purpose of this analysis was to identify, analyze, and report patterns (or themes) of planning and preparation considerations of students that scored less than the historic average score on the Pre-NAPLEX® exam. METHODS: This qualitative study was a retrospective, inductive thematic analysis of de-identified semi-structured interview field notes collected from student interviews for those students that scored less than the historic average score on the Pre-NAPLEX® exam. RESULTS: Ninety-one students were initially contacted based on their score on the Pre-NAPLEX® exam to participate in one-on-one virtual discussions (i.e., interviews) with faculty members. Fifty-two responded and participated with their responses analyzed and included in thematic categorization. Four major themes were identified during the analysis. These include 1) Organization and Messaging of NAPLEX® Preparation Efforts, 2) Time Management during Competing Obligations, 3) Test Taking Experience, and 4) Curricular Disconnect. CONCLUSION: Student performance on the NAPLEX licensing exam is of great concern to many colleges of pharmacy. As a result, many institutions are looking at root-causes for poor performance and working to implement structural changes at their institution to address these concerns. This investigation identified four major themes surrounding the preparation and planning for the Pre-NAPLEX® for students that scored less than the historic average score on the Pre-NAPLEX®. These include 1) Organization and Messaging of NAPLEX® Preparation Efforts, 2) Time Management during Competing Obligations, 3) Test Taking Experience, and 4) Curricular Disconnect. Each of these themes provides potentially actionable items to improve how students prepare and plan for the Pre-NAPLEX®, which may be translatable to informing actions to improve results on the actual NAPLEX exam itself.

Evaluating the Quality of Examination Items From the Pathophysiology, Drug Action, and Therapeutics Course Series.

OBJECTIVE: To determine the impact of item-writing flaws and cognitive level on student performance metrics in 1 course series across 2 semesters at a single institution. METHODS: Four investigators reviewed 928 multiple-choice items from an integrated therapeutics course series. Differences in performance metrics were examined between flawed and standard items, flawed stems and flawed answer choices, and cognitive levels. RESULTS: Reviewers found that 80% of the items were flawed, with the most common types being implausible distractors and unfocused stems. Flawed items were generally easier than standard ones, but the type of flaw significantly impacted the difficulty. Items with flawed stems had the same difficulty as standard items; however, those with flawed answer choices were significantly easier. Most items tested lower-level skills and have more flaws than higher-level items. There was no significant difference in difficulty between lower- and higher-level cognitive items, and higher-level items were more likely to have answer flaws than item flaws. CONCLUSION: Item-writing flaws differently impact student performance. Implausible distractors artificially lower the difficulty of questions, even those designed to assess higher-level skills. This effect contributes to a lack of significant difference in difficulty between higher- and lower-level items. Unfocused stems, on the other hand, likely increase confusion and hinder performance, regardless of the question's cognitive complexity.

Characterizing the Stability of Angiotensin II in 0.9% Sodium Chloride Using High Performance Liquid Chromatography and Liquid Chromatography Tandem Mass Spectrometry.

Purpose: The purpose of this study was to evaluate the stability of angiotensin II in 0.9% sodium chloride for up to 5 days. Methods: We prepared angiotensin II dilutions, by aseptically diluting 2.5 mg (1 mL) in 249 mL 0.9% sodium chloride creating a solution of 10 000 ng/mL. Admixtures were stored under refrigeration (5 ± 3°C). Stability of the dilution was assessed by: preservation of clarity, consistency of pH, and retention of concentration. Solutions were sampled at times 0, 24, 48, 72, 96, 120 hours. Solutions were analyzed via High-Performance Liquid Chromatography (HPLC-UV) and Liquid Chromatography Mass Spectrometry (LC-MS/MS). Retention of concentration was set a priori at > 90% of initial concentration. Results: Clarity, color, and pH at all sample time points remained constant. Both methods of analysis confirmed similar results. When stored under refrigeration, the concentration of angiotensin II solution remained above 90% of initial concentration throughout the entire sampling period. Conclusions: Angiotensin II in 0.9% sodium chloride stored in infusion bags under refrigeration (5 ± 3°C) maintained at least 90% of their original concentrations for up to 5 days. Stability was also demonstrated based on turbidity, color, and pH assessment.

Prospective observational study to validate a next-generation sequencing blood RNA signature to predict early kidney transplant rejection.

The objective of this study was to validate the performance of Tutivia, a peripheral blood gene expression signature, in predicting early acute rejection (AR) post-kidney transplant. Recipients of living or deceased donor kidney transplants were enrolled in a nonrandomized, prospective, global, and observational study (NCT04727788). The main outcome was validation of the area under the curve (AUC) of Tutivia vs serum creatinine at biopsy alone, or Tutivia + serum creatinine at biopsy. Of the 151 kidney transplant recipients, the mean cohort age was 53 years old, and 64% were male. There were 71% (107/151) surveillance/protocol biopsies and 29% (44/151) for-cause biopsies, with a 31% (47/151) overall rejection rate. Tutivia (AUC 0.69 [95% CI: 0.59-0.77]) and AUC of Tutivia + creatinine at biopsy (0.68 [95% CI: 0.59-0.77]) were greater than the AUC of creatinine at biopsy alone (0.51.4 [95% CI: 0.43-0.60]). Applying a model cut-off of 50 (scale 0-100) generated a high- and low-risk category for AR with a negative predictive value of 0.79 (95% CI: 0.71-0.86), a positive predictive value of 0.60 (95% CI: 0.45-0.74), and an odds ratio of 5.74 (95% CI: 2.63-12.54). Tutivia represents a validated noninvasive approach for clinicians to accurately predict early AR, beyond the current standard of care.

Pharmacokinetics and dialytic clearance of baricitinib during in vivo continuous venovenous haemodialysis in a patient with COVID-19.

OBJECTIVES: To date, there are no published pharmacokinetic (PK) data for baricitinib in critically ill patients requiring continuous renal replacement therapy. This paper describes in detail the plasma PK and dialytic clearance of baricitinib in a patient infected with coronavirus disease 2019 (COVID-19) requiring continuous renal replacement therapy in order to suggest dosing strategies in this population. METHODS: Baricitinib 2 mg daily was used for the treatment of COVID-19 in a critically ill patient on continuous venovenous haemodialysis (CVVHD). Prefiltration plasma drug concentrations of baricitinib were measured at hours 1, 2, 12, and 24 after drug administration. Postfiltration and ultrafiltrate concentrations were collected at hour 24. RESULTS: Plasma PK parameters of baricitinib in this patient were as follows: maximum plasma concentration (Cmax), 20.98 ng/mL; minimum plasma concentration (Cmin), 9.84 ng/mL; half-life (t1/2), 23.85 h; apparent volume of distribution at the steady state (Vss), 99.42 L; total clearance at the steady state (CLss), 2.89 L/h; and area under the concentration-time curve (AUC0-∞), 692.14 ng · h/mL. The saturation coefficient for baricitinib at 24 h after administration was 0.607. The transmembrane clearance of baricitinib by CVVHD running at a flow rate of 2 L/h was 1.21 L/h, representing 41.9% of the total clearance of baricitinib. CONCLUSIONS: In a critically ill COVID-19 patient on CVVHD, a 2-mg dose of baricitinib achieves a Cmax comparable with healthy subjects, but total clearance was reduced to about 20%. Larger studies exploring multiple patients and dialysis modes are needed to determine the optimal dosing strategy for baricitinib in this patient population.

Catecholamine Vasopressor Exposure Is Associated With Early Poor Allograft Function and Adverse Events in Living Donor Kidney Transplant Recipients.

BACKGROUND: Hypoperfusion leads to allograft injury during kidney transplantation. Catecholamine vasopressors are used to maintain blood pressure in the perioperative period but have demonstrated negative outcomes in the deceased-donor kidney transplant population. Little is known regarding living donor kidney transplants (LDKTs) and vasopressor use. The aim of this study is to describe the incidence of vasopressor use in LDKT and characterize its effects on allograft function and patient outcomes. METHODS: This retrospective, observational cohort study included adult patients who underwent an isolated LDKT between August 1, 2017, and September 1, 2018. Patients were divided into those who received perioperative vasopressors and those who did not. The primary objective was to compare allograft function between LDKT recipients that received vasopressors and those who did not. Secondary outcomes included safety endpoints and the identification of clinical variables associated with vasopressor use. RESULTS: A total of 67 patients received an LDKT during the study period. Of those, 25 (37%) received perioperative vasopressors, and 42 (62%) did not. Poor graft function, as defined by the development of slow or delayed graft function, occurred more frequently in patients receiving perioperative vasopressors compared with those who did not (6 [24%] vs 1 [2.4%], P = .016). In multivariable regression modeling, only perioperative vasopressors were statistically significantly associated with poor graft function. In addition, patients exposed to vasopressors experienced more postoperative arrhythmias (8 [32%] vs 1 [4.8%], P = .0025). CONCLUSION: Using perioperative vasopressors was independently associated with worsened early renal allograft function, including delayed graft function and adverse events in the LDKT population.

Retrospective evaluation of LCP-tacrolimus (Envarsus XR) dosing in de novo kidney transplant.

INTRODUCTION: Tacrolimus is known to exhibit significant inter- and intra-patient pharmacokinetic (PK) and pharmacodynamic (PD) variability regarding therapeutic response. LCP-tacrolimus (LCPT-Envarsus XR) was approved in 2018 for use as a de novo immunosuppressive agent in kidney transplants, but there is limited evidence to guide de novo dosing of LCPT in patients with obesity. The primary objective of this study was to evaluate the impact of different calculated weight-based de novo LCPT dosing on early transplant outcomes. METHODS: This was a retrospective study of patients with obesity (BMI ≥ 30 kg/m2 ) who received a kidney transplant at the University of Illinois Hospital and Health System (UIH), between March 2019 and March 2021. Subjects were included if were age 18 years or older and received de novo LCPT throughout index hospitalization. The primary endpoint of this study was to compare correlations between the first tacrolimus trough level and dosing weight strategy (e.g., TBW, AdjBW, IBW). RESULTS: There was a statistically significant, though modest, correlation between all three dosing strategies and the first tacrolimus trough level (TBW correlation coefficient = .431, p < .001; AdjBW correlation coefficient = .455, p < .001; IBW correlation coefficient = .465; p < .001). In regression modeling for supratherapeutic levels each additional .01 mg/kg increase in dose by TBW, AdjBW, and IBW increased the odds of a supratherapeutic level by 1.46, 1.34, and 1.24, respectively (p < .001). CONCLUSIONS: The use of LCPT in kidney transplant recipients with obesity dosed using TBW demonstrated the strongest correlation with initial supratherapeutic tacrolimus levels. Larger prospective studies are needed to investigate the further impact of body weight on dosing regimens in the obese population.

A Multimedia Evaluation of Pharmacy Faculty PowerPoint Slides in a Critical Care Course.

OBJECTIVES: To conduct a pilot investigation about the alignment between didactic multimedia materials utilized by pharmacy faculty, with Mayer's Principles for Multimedia Learning and faculty characteristics associated with greater alignment. METHODS: An investigatory systematic process was used which included a modified Learning Object Review Instrument (LORI) to evaluate the faculty video-recorded lectures for alignment with Mayer's Principles of Multimedia Learning, hence capturing the number and type of misalignments. Correlations were performed to evaluate the association between faculty characteristics; and ratings and proportions of misalignments. RESULTS: Five hundred fifty-five PowerPoint slides of 13 lectures from 13 faculty members were reviewed. The average (SD) LORI score per slide was 4.44 (0.84) out of 5 with an average score per lecture ranging from 3.83 (0.96) to 4.95 (0.53). Across all lecture slides, misalignments with multimedia principles were captured in 20.2% of slides. For each lecture, the average percentage of misalignments was 27.6% ranging from 0% to 49%. Principal misalignments included violation of the principles of coherence (66.1%), signaling (15.2%), and segmenting (8%). No faculty characteristics were significantly associated with LORI ratings or proportion of misalignments within lectures. CONCLUSIONS: Faculty had high LORI ratings for their multimedia material but these varied significantly between lectures. Misalignments with multimedia principles were identified and were related primarily to extraneous processing. These misalignments, when addressed, have the potential to improve learning, thus suggesting an opportunity for the faculty to develop ways to optimize multimedia educational delivery. Future investigation is needed to clarify how clinical pharmacy faculty can develop multimedia material and the impact of faculty development on the application of multimedia principles and learning outcomes.

Comparison of thrombotic and clinical outcomes in SARS-CoV-2-pneumonia versus other viral pneumonia in an urban academic medical center.

BACKGROUND: Infection with viral pneumonia (PNA) is known to offset the coagulation cascade. Recent studies assessing novel SARS-CoV-2 infection observed a high frequency of systemic thrombotic events resulting in ambiguity if severity of infection or specific viral strain drive thrombosis and worsen clinical outcomes. Furthermore, limited data exists addressing SARS-CoV-2 in underrepresented patient populations. OBJECTIVES: Assess clinical outcomes events and death in patients diagnosed with SARS-CoV-2 pneumonia compared to patients with other types of viral pneumonia. METHODS: Retrospective cohort study evaluated electronic medical records in adult patients admitted to University of Illinois Hospital and Health Sciences System (UIHHSS) with primary diagnosis of SARS-CoV-2 PNA or other viral (H1N1 or H3N2) PNA between 10/01/2017 and 09/01/2020. Primary composite outcome was the following event incidence rates: death, ICU admission, infection, thrombotic complications, mechanical ventilation, renal replacement therapy, and major bleeding. RESULTS: Of 257 patient records, 199 and 58 patients had SARS-CoV-2 PNA and other viral PNA, respectively. There was no difference in primary composite outcome. Thrombotic events (n = 6, 3%) occurred solely in SARS-CoV-2 PNA patients in the ICU. A significantly higher incidence of renal replacement therapy (8.5% vs 0%, p=0.016) and mortality (15.6% vs 3.4%, p=0.048) occurred in the SARS-CoV-2 PNA group. Multivariable logistic regression analysis revealed age, presence of SARS-CoV-2, and ICU admission, aOR 1.07, 11.37, and 41.95 respectively, was significantly associated with mortality risk during hospitalization; race and ethnicity were not. CONCLUSION: Low overall incidence of thrombotic events occurred only in the SARS-CoV-2 PNA group. SARS-CoV-2 PNA may lead to higher incidence of clinical events than those observed in H3N2/H1N1 viral pneumonia, and that race/ethnicity does not drive mortality outcomes.

Effects of angiotensin II in the management of perioperative hypotension in kidney transplant recipients.

BACKGROUND: Due to the mechanisms of action of conventional catecholamine vasopressors, there is increased risk of renal allograft injury and adverse events in transplant recipients with fluid-refractory distributive shock during the perioperative period. As such, mechanistically alternative vasopressors like angiotensin II (ATII) may avoid these complications, but there is an absence of data supporting use in this population. METHODS: This was a single-center, single-arm, open-label, phase 4 study conducted as a 1-year pilot of 20 adult renal transplant recipients receiving ATII as their first continuous infusion vasopressor in the perioperative period. The study aim was to systematically assess the safety and hemodynamic effects of ATII. Safety was assessed based on the incidence of adverse events. Hemodynamic effect was assessed by the achievement of per protocol hemodynamic goals (i.e., SBP ≥120 mmHg) and the need for adjunct vasopressors. RESULTS: Most cases involved deceased donors (70%), with a corresponding mean (SD) cold ischemia time of 14.7 (8.6) h. Over a surgery duration of 5.3 (1.2) h, subjects received 3.2 (2.0) L of total volume resuscitation prior to ATII initiation. No adverse events were directly related to ATII administration. Throughout this period, ATII was utilized for a median of 1.0 (IQR, 1.5) h intraoperatively (N = 7), 26.5 (IQR, 84.8) h postoperatively (N = 4), and 63.8 (IQR, 57.8) h in subjects who required ATII both intra- and postoperatively (N = 9). Only one of the 20 patients needed adjunct continuous infusion vasopressors in addition to ATII. CONCLUSIONS: Based on the observations of this pilot study, ATII is a safe and effective vasopressor option for renal transplant recipients requiring perioperative hypotension reversal.

Perioperative Vasopressors are Associated with Delayed Graft Function in Kidney Transplant Recipients in a Primarily Black and Hispanic Cohort.

Introduction: Negative outcome studies of vasopressors in kidney transplant have not focused on patient populations that are predominantly Black or Hispanic. Project Aims: The evaluation sought to investigate the independent impact of perioperative vasopressors on postoperative renal allograft function in a sample drawn from a primarily Black and Hispanic population. Design: Retrospective, observational, single-center evaluation of patients > 18 years old who underwent kidney transplantation comparing outcomes based on vasopressor exposure. Results: The study included 150 patients of which 60 received vasopressors. The primary outcome differed between groups with delayed graft function occurring in 17(28%) versus 11(12.2%) occurring more often in those that received perioperative vasopressors (P = 0.02). The serum creatinine at postoperative day 7 was higher (2.69 vs1.52 mg/dL, P = 0.004), postoperative day 7 eGFR was worse (27.3 vs 52.9 mL/min/1.73m2, P = 0.002) in patients who received vasopressors. Patients who received perioperative vasopressors experienced more postoperative arrhythmias (15% vs 8%, P = 0.007), insulin infusion therapy (26.7% vs 13.3%, P = 0.04), and increased hospital length of stay (6 days vs 5 days, P = 0.006). Using IPWRA, patients receiving vasopressors were more likely to experience delayed function, relative risk difference of 22% (95% CI:0.08-0.35;P = 0.002) and in multivariate logistic regression modeling, an increased odds ratio of 3.2 (95% CI:1.1-8.62;P = 0.022). Conclusions: The use of perioperative vasopressors was independently associated with worsened early renal allograft function including delayed graft function, increased adverse events such as postoperative arrhythmias, and longer ICU length of stay. Further investigation is needed surrounding vasopressor use in this population.

Hemodynamic Effects of Ketamine Compared With Propofol or Dexmedetomidine as Continuous ICU Sedation.

BACKGROUND: Ketamine has seen increased use for sedation in the intensive care unit. In contrast to propofol or dexmedetomidine, ketamine may provide a positive effect on hemodynamics. OBJECTIVE: The objective of this study was to compare the development of clinically significant hypotension or bradycardia (ie, negative hemodynamic event) between critically ill adults receiving sedation with ketamine and either propofol or dexmedetomidine. METHODS: This was a retrospective cohort study of adults admitted to an intensive care unit at an academic medical center between January 2016 and January 2021. RESULTS: Patients in the ketamine group (n = 78) had significantly less clinically significant hypotension or bradycardia compared with those receiving propofol or dexmedetomidine (n = 156) (34.6% vs 63.5%; P < 0.001). Patients receiving ketamine also experienced smaller degree of hypotension observed by percent decrease in mean arterial pressure (25.3% [17.4] vs 33.8% [14.5]; P < 0.001) and absolute reduction in systolic blood pressure (26.5 [23.8] vs 42.0 [37.8] mm Hg; P < 0.001) and bradycardia (15.5 [24.3] vs 32.0 [23.0] reduction in beats per minute; P < 0.001). In multivariate logistic regression modeling, receipt of propofol or dexmedetomidine was the only independent predictor of a negative hemodynamic event (odds ratio [OR]: 3.3, 95% confidence interval [CI], 1.7 to 6.1; P < 0.001). CONCLUSION AND RELEVANCE: Ketamine was associated with less clinically relevant hypotension or bradycardia when compared with propofol or dexmedetomidine, in addition to a smaller absolute decrease in hemodynamic parameters. The clinical significance of these findings requires further investigation.

Poor guideline adherence in a real-world evaluation of hypertensive emergency management.

BACKGROUND: The American College of Cardiology and American Heart Association define hypertensive emergency (HTN-E) as a systolic blood pressure greater than 180 mmHg or a diastolic blood pressure greater than 120 mmHg with evidence of end-organ damage (EOD). Based on expert opinion, current guidelines recommend antihypertensive therapy to reduce blood pressure (BP) at specific hourly rates to reduce progression of EOD, outlined by four criteria. Our goal was to describe compliance with guideline recommendations for early management of HTN-E and to analyze safety outcomes related to pharmacologic intervention. METHODS: This was a retrospective chart review including patients presenting to the emergency department with HTN-E between September 2016 and August 2020. We excluded patients with a compelling indication for altered therapeutic goals (e.g. acute aortic dissection, hemorrhagic or ischemic stroke, and pheochromocytoma). The primary outcome was complete adherence with guideline recommendations in the first 24 h. RESULTS: Of 758 screened records, 402 were included. Mean age was 54 years and majority Black race (72%). Overall, total adherence was poor (<1%): 30% received intravenous therapy within 1 h, 64% achieved 1-h BP goals, 44% achieved 6-h goals, and 9% had appropriate 24-h maintenance BP. Hypotensive events (N = 67) were common and antihypertensive-associated EOD (N = 21) did occur. Predictors of hypotension include treatment within 1 h and management with continuous infusion medication. CONCLUSIONS: Current practice is poorly compliant with guideline criteria and there are risks associated with recommended treatments. Our results favor relaxing the expert opinion-based recommendations.

Pharmacokinetics and dialytic clearance of apixaban during in vitro continuous renal replacement therapy.

BACKGROUND: To evaluate the transmembrane clearance (CLTM) of apixaban during modeled in vitro continuous renal replacement therapy (CRRT), assess protein binding and circuit adsorption, and provide initial dosing recommendations. METHODS: Apixaban was added to the CRRT circuit and serial pre-filter bovine blood samples were collected along with post-filter blood and effluent samples. All experiments were performed in duplicate using continuous veno-venous hemofiltration (CVVH) and hemodialysis (CVVHD) modes, with varying filter types, flow rates, and point of CVVH replacement fluid dilution. Concentrations of apixaban and urea were quantified via liquid chromatography-tandem mass spectrometry. Plasma pharmacokinetic parameters for apixaban were estimated via noncompartmental analysis. CLTM was calculated via the estimated area under the curve (AUC) and by the product of the sieving/saturation coefficient (SC/SA) and flow rate. Two and three-way analysis of variance (ANOVA) models were built to assess the effects of mode, filter type, flow rate, and point of dilution on CLTM by each method. Optimal doses were suggested by matching the AUC observed in vitro to the systemic exposure demonstrated in Phase 2/3 studies of apixaban. Linear regression was utilized to provide dosing estimations for flow rates from 0.5-5 L/h. RESULTS: Mean adsorption to the HF1400 and M150 filters differed significantly at 38 and 13%, respectively, while mean (± standard deviation, SD) percent protein binding was 70.81 ± 0.01%. Effect of CVVH point of dilution did not differ across filter types, although CLTM was consistently significantly higher during CRRT with the HF1400 filter compared to the M150. The three-way ANOVA demonstrated improved fit when CLTM values calculated by AUC were used (adjusted R2 0.87 vs. 0.52), and therefore, these values were used to generate optimal dosing recommendations. Linear regression revealed significant effects of filter type and flow rate on CLTM by AUC, suggesting doses of 2.5-7.5 mg twice daily (BID) may be needed for flow rates ranging from 0.5-5 L/h, respectively. CONCLUSION: For CRRT flow rates most commonly employed in clinical practice, the standard labeled 5 mg BID dose of apixaban is predicted to achieve target systemic exposure thresholds. The safety and efficacy of these proposed dosing regimens warrants further investigation in clinical studies.

Comparison of Vasopressor Duration in Septic Shock Patients With and Without Cirrhosis.

BACKGROUND: Patients with cirrhosis have immune dysfunction, altered inflammatory response, and hemodynamic changes which increase risk of septic shock and potentially prolong management with fluids, vasopressors, and other therapies. Due to limited available guidance, this study aimed to characterize vasopressor use in patients with cirrhosis in relation to patients without cirrhosis in septic shock. METHODS: This was a retrospective matched cohort analysis of 122 patients admitted to the intensive care unit (ICU) at an academic medical center from January 2015 to November 2017. Patients were grouped based on the presence or absence of cirrhosis and matched based on severity of illness scoring. The primary outcome was vasopressor duration. Secondary comparisons included total vasopressor requirement, length of hospital and ICU stay, in-hospital mortality, change in organ function, and discharge disposition. RESULTS: The group with cirrhosis had significantly longer median (interquartile range [IQR]) durations of vasopressor therapy compared with the group without cirrhosis (86.0 [42.0-164.5] vs 39.0 [14.5-82.0] hours; P = 0.003) leading to increased median (IQR) vasopressor exposure (71.7 [15.5-239.5] vs 24.7 [5.3-77.9] mg norepinephrine [NE] equivalents; P = 0.003). No difference was found in in-hospital mortality between groups. However, regression analysis showed vasopressor exposure was associated with in-hospital mortality. CONCLUSION AND RELEVANCE: Patients with cirrhosis in septic shock have increased vasopressor durations and overall requirements compared with patients without cirrhosis. Increased durations and requirements is associated with poorer outcomes independent of presence of cirrhosis. Future studies are needed to improve vasopressor treatment strategies and end points utilized in cirrhosis.

Safety and Efficacy of Apixaban For Therapeutic Anticoagulation in Critically Ill ICU Patients with Severe COVID-19 Respiratory Disease.

Introduction Despite the use of unfractionated heparin (UFH) or low molecular weight heparin (LMWH), rates of thromboembolic disease, and subsequent morbidity and mortality remain unacceptably high in patients with severe novel coronavirus disease 2019 (COVID-19) disease. Direct oral anticoagulants (DOACs), such as apixaban, have numerous purported benefits although the safety and efficacy of their use in intensive care unit (ICU) patients with severe COVID-19 has yet to be evaluated. Materials and Methods Single-center, retrospective cohort study of 21 ICU patients with severe COVID-19 respiratory disease treated with apixaban for atrial fibrillation (AFib), venous thromboembolism (VTE), catheter-induced thrombosis, and/or COVID-19-induced coagulopathy. The primary objective was to evaluate the incidence of bleeding events and secondary objectives included thromboembolic events, coagulation parameters, and mortality. Results Ninety percent of patients were non-White, 43% were obese, 90% had acute respiratory distress syndrome, and 76% required mechanical ventilation. Nearly half of (47.6%) also experienced renal dysfunction and required renal replacement therapy. Eighty-six percent of patients received prophylaxis or treatment with UFH or LMWH within the 24-hour period prior to apixaban initiation. Patients were initiated on apixaban for the treatment of suspected or confirmed VTE (67%) or AFib (33%). All coagulation parameters remained abnormal but stable throughout the 10-day monitoring period. No patients experienced any major bleeding events or thrombosis throughout the study period. There were four deaths during the follow-up period, all deemed unrelated to coagulopathy or bleeding. Conclusion Apixaban appeared safe and efficacious in ICU patients with severe COVID-19 disease. These data encourage future trials seeking to optimize anticoagulation strategies in patients with severe COVID-19.

A Pilot Study of End-Tidal Carbon Dioxide in Prediction of Inhospital Cardiac Arrests.

A validated means to predict inhospital cardiac arrest is lacking. The purpose of this study was to evaluate the changes in end-tidal carbon dioxide, as it correlates with the progression to inhospital cardiac arrest in ICU patients. DESIGN SETTING AND PATIENTS: Single-center, retrospective cohort study of mechanically ventilated ICU patients (age > 18 yr old) having inhospital cardiac arrest with advanced cardiac life support and continuous end-tidal carbon dioxide monitoring at a single academic center from 2014 to 2017. Demographics, clinical variables, and outcomes were collected. End-tidal carbon dioxide was collected from 5 to 2,880 minutes before inhospital cardiac arrest. Data were analyzed using descriptive statistics, and model estimates were generated using a repeated-measures categorical model with restricted maximum likelihood estimation and fully specified (autoregressive) covariance to assess the effect of time on changes in end-tidal carbon dioxide. MEASUREMENTS AND MAIN RESULTS: A total of 788 patients were identified and 104 met inclusion criteria, where 62% were male with an average age of 58.5 years. Seventy-four percent required vasopressors and 72% experienced pulseless electrical activity. Mean end-tidal carbon dioxide 5 minutes prior to inhospital cardiac arrest was significantly lower than all evaluated time points except 180 minutes (p < 0.05). One patient survived to hospital discharge. In multivariate logistic regression modeling for return of spontaneous circulation, a greater change in the prearrest end-tidal carbon dioxide maximum to prearrest end-tidal carbon dioxide minimum was associated with a decreased likelihood of return of spontaneous circulation (odds ratio 0.903; 95% CI, 0.832-0.979; p = 0.014). Additionally, a change from prearrest end-tidal carbon dioxide maximum to prearrest end-tidal carbon dioxide minimum greater than 17 mm Hg was associated with a decreased likelihood of return of spontaneous circulation and odds ratio 0.150; 95% CI, 0.036-0.66; p = 0.012). CONCLUSIONS: Mean end-tidal carbon dioxide is significantly lower immediately before inhospital cardiac arrest. The statistical and clinical significance of end-tidal carbon dioxide may highlight its utility for predicting inhospital cardiac arrest in ICU patients. Comparison analysis and modeling explorations in a larger cohort are needed.