Impact of Piperacillin-Tazobactam Dosing in Septic Shock Patients Using Real-World Evidence: An Observational, Retrospective Cohort Study.

BACKGROUND: Sepsis and septic shock are associated with significant morbidity and mortality. Rapid initiation of appropriate antibiotic therapy is essential, as inadequate therapy early during septic shock has been shown to increase the risk of mortality. However, despite the importance of appropriate antibiotic initiation, in clinical practice, concerns for renal dysfunction frequently lead to antibiotic dose reduction, with scant evidence on the impact of this practice in septic shock patients. OBJECTIVE: The purpose if this article is to investigate the rate and impact of piperacillin-tazobactam dose adjustment in early phase septic shock patients using real-world electronic health record (EHR) data. METHODS: A multicenter, observational, retrospective cohort study was conducted of septic shock patients who received at least 48 hours of piperacillin-tazobactam therapy and concomitant receipt of norepinephrine. Subjects were stratified into 2 groups according to their cumulative 48-hour piperacillin-tazobactam dose: low piperacillin-tazobactam dosing (LOW; <27 g) group and normal piperacillin-tazobactam dosing (NORM; ≥27 g) group. To account for potential confounding variables, propensity score matching was used. The primary study outcome was 28-day norepinephrine-free days (NFD). RESULTS: In all, 1279 patients met study criteria. After propensity score matching (n = 608), the NORM group had more median NFD (23.9 days [interquartile range, IQR: 0-27] vs 13.6 days [IQR: 0-27], P = 0.021). The NORM group also had lower rates of in-hospital mortality/hospice disposition (25.9% [n = 79] vs 35.5% [n = 108]), P = 0.014). Other secondary outcomes were similar between the treatment groups. CONCLUSIONS AND RELEVANCE: In the propensity score-matched cohort, the NORM group had significantly more 28-day NFD. Piperacillin-tazobactam dose reduction in early phase septic shock is associated with worsened clinical outcomes. Clinicians should be vigilant to avoid piperacillin-tazobactam dose reduction in early phase septic shock.

Evaluating the incidence of engraftment syndrome with different melphalan formulations in adult multiple myeloma and immunoglobulin light chain amyloidosis patients undergoing autologous hematopoietic cell transplantation.

BACKGROUND: Engraftment syndrome (ES) is a common complication of autologous hematopoietic cell transplantation (HCT). The difference in incidence of ES between melphalan formulations has not been widely reported throughout the literature and would allow for a more comprehensive understanding of the advantages and disadvantages of both melphalan formulations. PATIENTS AND METHODS: This retrospective, single-center, observational study evaluated 83 adult multiple myeloma and immunoglobulin light chain amyloidosis patients who received either propylene glycol-containing (PG) or propylene glycol-free (PG-free) melphalan 140 mg/m2 as single-agent conditioning chemotherapy for autologous HCT from May 31, 2015 to May 31, 2019. The primary outcome was to assess the incidence of ES, as defined using the Maiolino criteria, with both melphalan formulations. Secondary outcomes included an analysis of potential risk factors for the development of ES, as well as an evaluation of overall length of stay (LOS). RESULTS: The incidence of ES for PG and PG-free melphalan did not differ significantly, 14/39 (35.9%) and 12/44 (27.3%) (P = 0.4), respectively. No potential risk factors for ES were identified on multivariate logistic regression analysis. A statistically significant difference in number of days to engraftment was identified for PG and PG-free melphalan, 15.56 vs. 13.82 days (P = 0.01), respectively; although, this did not translate to a decrease in LOS, 19.9 vs. 18.59 days (P = 0.14). CONCLUSIONS: The incidence of ES did not differ significantly between melphalan formulations. Future research is needed to determine whether the faster time to engraftment seen with PG-free melphalan may translate to a decrease in LOS.

Recent Updates in the Pharmacological Management of Sepsis and Septic Shock: A Systematic Review Focused on Fluid Resuscitation, Vasopressors, and Corticosteroids.

OBJECTIVE: Describe recent developments in the pharmacological management of sepsis and septic shock, focusing on fluid resuscitation, vasopressors, and corticosteroids. DATA SOURCES: A literature search limited to randomized controlled trials written in the English language reporting mortality and other clinically relevant outcomes that were published from July 1, 2016, to August 31, 2018, in patients aged ≥ 18 years. Titles and abstracts were reviewed for relevance. References for pertinent review articles were also reviewed. STUDY SELECTION AND DATA EXTRACTION: Relevant randomized controlled trials conducted in patients meeting the pre-defined inclusion criteria were considered for inclusion. DATA SYNTHESIS: From an initial search that identified 147 studies, 14 original research studies met inclusion criteria and were included in this review. Risk of bias (ROB) was assessed using the Revised Cochrane ROB assessment tool, with most included studies having a low ROB. Relevance to Patient Care and Clinical Practice: Sepsis and septic shock pose a significant burden on public health. Despite advances in our understanding of sepsis, mortality remains unacceptably high. Recent developments in the pharmacological management of septic shock have focused on determining optimal composition and dosage of fluid resuscitation, enhanced use of vasopressor therapy, and clarifying the role of corticosteroids. This systematic review will provide recommendations for application to practice focusing on recent research on these topics. CONCLUSIONS: Although recent developments in the pharmacological management of sepsis are encouraging, clinicians must be keen to utilize patient-specific factors to guide therapy and continue to strive to address the remaining unanswered questions.

Association of deep-vein thrombosis (DVT) with missed doses of prophylactic antithrombotic medications in ICU patients: a case-control study.

BACKGROUND: Medications for prevention of venous thromboembolism (VTE) are routinely prescribed in critically ill patients. OBJECTIVE: To identify any association between missed doses of VTE prophylaxis medications and acute, in-hospital deep-vein thrombosis (DVT). METHODS: Case-control study in hospitalized adult patients at high risk for developing VTE, defined as an ICU length of stay (LOS) of at least 24 hours. Cases were defined as patients with acute DVT during hospitalization, and controls were patients with no documented DVT. Multivariate logistic regression was used to assess the odds of acute DVT in patients with any missed dose of prophylactic antithrombotic medication. RESULTS: Of 920 patients, 59 (6.4%) experienced an acute, in-hospital DVT. Overall, 64% of patients missed at least 1 dose of VTE prophylaxis medication, and 33% missed more than 3 doses. In the univariate analysis, there was no significant association between any missed dose of prophylaxis medication and acute DVT (odds ratio [OR] = 0.96; CI = 0.56-1.7). Multivariate logistic regression modeling confirmed no association between missed doses of pharmacological VTE medications and acute DVT (OR = 0.69 [0.39-1.2]; P = 0.21). Prolonged hospital LOS was associated with increased odds of acute DVT (LOS = 4-6 days; OR = 0.75 [0.21-2.6]; LOS = 7-13 days; OR = 2.3 [0.9-5.9]; and LOS = ≥14 days; OR = 6.4 [2.6-15.9]). CONCLUSION: We found no evidence of a relationship between any missed dose of prophylactic antithrombotic medication and development of acute DVT. The odds of acute DVT increased in patients with prolonged hospital LOS.

Risk Factors for Delirium and Association of Antipsychotic Use with Delirium Progression in Critically Ill Trauma Patients.

BACKGROUND: Delirium occurs frequently in critically ill and injured patients and is associated with significant morbidity and mortality. Limited data exists on the risk factors for developing delirium in critically ill trauma patients and the effect of antipsychotic (AP) medications on delirium progression. OBJECTIVE: The objective of this study is to determine the incidence of delirium in critically ill trauma versus non-trauma surgical patients and determine if the presence of trauma was associated with intensive care unit (ICU) delirium. Secondary outcomes included identifying risk factors for delirium and determining the impact of AP medication use on delirium progression in critically ill trauma patients. METHODS: This retrospective review studies adult trauma/surgical ICU patients admitted between May 2017-July 2018 to a level I trauma and tertiary referral center. Regression modeling was used to determine the impact of AP use on delirium-free days. RESULTS: Delirium was more common in critically ill trauma patients versus non-trauma surgical ICU patients [54/157 (34.4%) vs 42/270 (15.6%), P < .001]. Of the 54 trauma patients with delirium, 28 (52%) received an AP medication for delirium treatment and in the multiple linear regression analysis, AP use was significantly associated with fewer delirium-free days (P = .02). DISCUSSION: Higher admission sequential organ failure assessment scores and increased length of stay were significantly associated with delirium onset in critically ill trauma patients. Use of AP medications for delirium treatment in this population had a negative impact on delirium-free days.

Perceived versus actual sedation practices in adult intensive care unit patients receiving mechanical ventilation.

BACKGROUND: With drug shortages, newer sedative medications, and updates in research, management of sedation and delirium in patients receiving mechanical ventilation continues to evolve. OBJECTIVE: To compare perceived and actual sedation practices for adults receiving mechanical ventilation in intensive care units (ICUs). METHODS: This was a multicenter, 2-part study conducted in adult ICUs in US hospitals. It included a sedation practice survey completed by ICU pharmacists and an observational study evaluating actual sedation practices over a 24-hour period. RESULTS: Surveys were completed for 85 ICUs; observational data for 496 patients were collected. Preferred sedatives from the survey data were propofol (short-term); propofol, midazolam, or lorazepam (intermediate); and lorazepam (long-term). Propofol was the most commonly used agent overall during the observational period (primarily for short-term and intermediate-length sedation); midazolam was the most commonly used for long-term sedation. Fentanyl was the preferred analgesic, and haloperidol and quetiapine were the preferred antipsychotics. Sedation treatment algorithms were used in only 50% of observed ICUs. Use of daily interruption of sedation was perceived to be 66% but was only observed in 36% of patients. Monitoring for delirium was reported among 25% of those surveyed but was observed in only 10% of patients. Targeted sedation goals were most frequently achieved when a treatment algorithm was used or when an opiate infusion was the single agent used for sedative management. CONCLUSIONS: These data suggest differences in perceived and actual sedation practice in the US, as well as underutilization of evidence-based interventions. Most notable was the limited use of sedation treatment algorithms, daily interruption of sedation, and monitoring for delirium. Individual sedation and delirium protocols should be evaluated and updated based on evidence-based recommendations.

Loop diuretic use following fluid resuscitation in the critically ill.

PURPOSE: To identify the incidence of continuation of newly initiated loop diuretics upon intensive care unit (ICU) and hospital discharge and identify factors associated with continuation. METHODS: This was a single-center retrospective study using electronic health records in the setting of adult ICUs at a quaternary care academic medical center. It involved patients with sepsis admitted to the ICU from January 1, 2014, to June 30, 2019, who received intravenous fluid resuscitation. The endpoints of interest were (1) the incidence of loop diuretic use during an ICU stay following fluid resuscitation, (2) continuation of loop diuretics following transition of care, and (3) potential factors associated with loop diuretic continuation after transition from the ICU. RESULTS: Of 3,591 patients who received intravenous fluid resuscitation for sepsis, 39.4% (n = 1,415) were newly started on loop diuretics during their ICU stay. Among patients who transitioned to the hospital ward from the ICU, loop diuretics were continued in 33% (388/1,193) of patients. At hospital discharge, 13.4% (52/388) of these patients were prescribed a loop diuretic to be used in the outpatient setting. History of liver disease, development of acute kidney injury, being on vasopressors while in the ICU, receiving blood products, and receiving greater than 90 mL/kg of bolus fluids were significant potential factors associated with loop diuretic continuation after transition from the ICU. CONCLUSION: New initiation of loop diuretics following intravenous fluid resuscitation in patients with sepsis during an ICU stay is a common occurrence. Studies are needed to assess the effect of this practice on patient outcomes and resource utilization.

Re-evaluation of cefepime or piperacillin-tazobactam to decrease use of carbapenems in extended-spectrum beta-lactamase-producing Enterobacterales bloodstream infections (REDUCE-BSI).

Objective: To re-examine the use of noncarbapenems (NCBPs), specifically piperacillin-tazobactam (PTZ) and cefepime (FEP), for extended-spectrum beta-lactamase-producing Enterobacterales bloodstream infections (ESBL-E BSIs). Design: Retrospective cohort study. Setting: Tertiary-care, academic medical center. Patients: The study included patients hospitalized between May 2016 and May 2019 with a positive blood culture for ESBL-E. Patients were excluded if they received treatment with antibiotics other than meropenem, ertapenem, PTZ, or FEP. Patients were also excluded if they were aged <18 years, received antibiotics for <24 hours, were treated for polymicrobial BSI, or received concomitant antibiotic therapy for a separate gram-negative infection. Methods: We compared CBPs with FEP or PTZ for the treatment of ESBL-E BSI. The primary outcome was in-hospital mortality. Secondary outcomes included clinical cure, microbiologic cure, infection recurrence, and resistance development. Results: Data from 114 patients were collected and analyzed; 74 (65%) patients received carbapenem (CBP) therapy and 40 (35%) patients received a NCBP (30 received FEP and 10 received PTZ). The overall in-hospital mortality was 6% (N = 7), with a higher death rate in the CBP arm than in the N-CBP arm, (8% vs 3%; P = .42). No difference in mortality was detected between subgroups with Pitt bacteremia score ≥4, those requiring ICU admission, those whose infections were cause by a nongenitourinary source or causative organism (ie, 76 had Escherichia coli and 38 had Klebsiella spp). We detected no differences in secondary outcomes between the groups. Conclusion: Compared to CBPs, FEP and PTZ did not result in greater mortality or decreased clinical efficacy for the treatment of ESBL-E BSI caused by susceptible organisms.

Impact of Early Postoperative Hydrocortisone Administration in Cardiac Surgical Patients After Cardiopulmonary Bypass.

BACKGROUND: The usefulness of glucocorticoids after cardiac surgery with cardiopulmonary bypass has been a matter of debate for many years. Exposure to cardiopulmonary bypass evokes the systemic inflammatory response syndrome in patients undergoing cardiac surgery. Intravenous glucocorticoids have been used to reduce proinflammatory cytokine release, slow leukocyte migration, and decrease capillary leak associated with cardiopulmonary bypass. OBJECTIVE: To assess the impact of early postoperative hydrocortisone administration on duration of vasoactive medication administration and the incidence of postoperative atrial fibrillation in cardiac surgical patients after cardiopulmonary bypass. METHODS: A retrospective cohort study (between July 1, 2004, and June 30, 2008) was conducted at a large, university-affiliated, tertiary-care medical center. One-hundred forty-seven patients who underwent cardiac surgery with cardiopulmonary bypass, 72 of whom received at least 1 dose of hydrocortisone (treatment), and 75 similar patients who did not receive hydrocortisone (control), were randomly selected. RESULTS: Cardiopulmonary bypass and aortic cross-clamp times were similar between treatment and control groups (128 vs 124 minutes, p = 0.56; 103 vs 98 minutes, p = 0.39). Patients who received hydrocortisone had a significantly shorter time to discontinuation of all vasoactive medications (79.6 vs 21.1 hours, p < 0.001), and less postoperative atrial fibrillation (OR 0.28, 95% CI 0.14 to 0.56, p < 0.001). Patients in the treatment group experienced significantly more hyperglycemia (89 vs 71%, p = 0.006); however, major and minor bleeding or infection rates did not differ significantly between groups. CONCLUSIONS: Patients treated with hydrocortisone after cardiac surgery with cardiopulmonary bypass experienced a significantly shorter time to discontinuation of all vasoactive medications and less postoperative atrial fibrillation than patients not treated with hydrocortisone. These benefits came at the expense of significantly more hyperglycemia.

Impact of Supplemental Material Use on Student Metacognitive Monitoring and Calibration.

Objective. To determine whether third year Doctor of Pharmacy students' self-reported use of optional supplemental material impacted their ability to accurately predict their performance on a low-stakes assessment.Methods. An instructor created optional supplemental material in the form of an online quiz. Students were asked to report whether they used the supplemental material and to predict and postdict their performance on an in-class assessment. The relative accuracy of the predictions and postdictions as well as the assessment grades and overall course grades were compared between students who reported using the supplemental material and those who reported not using the supplemental material.Results. More than half of the students (60%) reported using the supplemental material. Most students underpredicted their performance on the in-class assessment, but there was no difference in the accuracy of predictions based on supplemental material use or non-use (-1.2 vs -1.0) or on the postdictions (-1.3 vs. -1.0). Students who reported using the supplemental material performed better on both the low-stakes assessment (7.7 vs 7.2 out of 10) and overall in the course (87.0% vs 84.9%).Conclusion. Pharmacy students' self-reported use of optional supplemental material does not appear to impact their ability to accurately predict their performance on a low-stakes assessment.

Candida meningitis post Gliadel wafer placement successfully treated with intrathecal and intravenous amphotericin B.

OBJECTIVE: To report a case of Candida meningitis post Gliadel wafer (polifeprosan 20 with carmustine implant) placement successfully treated with the combination of intrathecal and intravenous amphotericin B. CASE SUMMARY: A 33-year-old white female with a history of recurrent oligodendroglioma was admitted to the neuroscience intensive care unit with acute mental status changes. Computed tomography of the head demonstrated a cystic dilation of the right frontoparietal tumor resection cavity with Gliadel wafers in place and the presence of a large fluid collection. The cavity was debrided surgically and a ventriculostomy catheter was left in place. Cerebrospinal fluid (CSF) cultures were positive for Candida albicans and methicillin-resistant coagulase-negative Staphylococcus spp. Antiinfective therapy with intrathecal and intravenous amphotericin B as well as flucytosine and vancomycin was started. The patient had subsequent improvement in clinical manifestations, resolution of CSF leukocytosis, and mycologic cure. DISCUSSION: Candida meningitis occurs primarily in the setting of immunosuppression, intravenous drug abuse and following neurosurgical procedures. Secondary bacterial and fungal infections have been reported following Gliadel wafer placement in patients with brain tumor resection. Candida meningitis has traditionally been treated with intravenous amphotericin B with or without oral flucytosine. There have been reports of treatment with intrathecal amphotericin B with variable clinical outcomes. CONCLUSIONS: This case demonstrates successful treatment of Candida meningitis post Gliadel wafer placement with the combination of intrathecal and intravenous amphotericin B. This treatment modality may provide an effective therapeutic option for other patients with Candida meningitis, especially those unresponsive to intravenous therapy.

Modification of the self-regulated strategy inventory-self report for blended and team-based learning.

INTRODUCTION: One of the primary missions of pharmacy education is to produce graduates with the foundations to develop into expert practitioners through continuous learning and reflection upon traditional and clinical experiences. This reflection process and the use of effective strategies to meet specific learning goals can be considered a form of self-regulated learning (SRL). The following study validates an inventory to assess SRL strategies in blended and team-based learning (TBL) environments. METHODS: A SRL strategy inventory was developed based upon the Self-Regulated Strategies Inventory-Self-Report (SRSI-SR) and new items designed for blended and TBL environments. Sixteen new items focused on leveraging the team to learn content, the use and misuse of video lectures and slides, and interaction with social media and the learning management system. Two hundred and thirty doctor of pharmacy students in the third professional year participated in the study. Twenty-eight items from the SRSI-SR and 16 new items were examined through a principal components analysis (PCA). RESULTS: The PCA indicated three distinct components; managing learning environment, maladaptive learning strategies, and seeking and learning information. The total inventory accounted for 46.36% of the score. Maladaptive learning strategies scores were moderately predictive of poor academic achievement in didactic coursework. CONCLUSIONS: The following study demonstrates the importance of reexamination and adaptation of educational inventories such as the SRSI-SR. This study provides specific insight into what maladaptive strategies may be limiting underperforming students from achieving greater success and mastery in the didactic curriculum.

Intensive Care Unit Delirium in Surgical Patients Is Associated with Upregulation in Tryptophan Metabolism.

INTRODUCTION: In intensive care unit (ICU) patients, delirium is frequent, occurs early in ICU admission, and is associated with poor outcomes. Risk models based on clinical factors have shown variable performance in terms of predictive ability. Identification of a candidate biomarker that associates with delirium may lead to a better understanding of disease mechanism, validation biomarker studies, and the ability to develop targeted interventions for prevention and treatment of delirium. This study analyzed metabolite concentrations early in the course of ICU admission to assess the association with delirium onset. METHODS: Within 24 hours of ICU admission, blood samples for global and targeted metabolomics analyses in adult surgical ICU patients were collected prospectively. Metabolites were determined using mass spectrometry/ultra-high-pressure liquid chromatography and analyzed in patients with delirium and a group of controls matched on age, sex, and admission Sequential Organ Function Assessment (SOFA) score. RESULTS: Patients in the study (65 per group) were a mean age of 59 years, had a median SOFA score of 6, and were most commonly admitted to the ICU following major trauma. In the delirium group, median onset of delirium was 3 (interquartile range 1-6) days, and the most common delirium subtype was mixed (56%). Kynurenic acid was significantly increased, and tryptophan concentration was significantly decreased in the delirium group (p=0.04). The ratio of kynurenine-to-tryptophan concentration was significantly higher in the delirium group (p=0.005). CONCLUSIONS: Evidence of upregulation was found in the tryptophan metabolic pathway in delirious patients because tryptophan concentrations were lower, tryptophan metabolites were higher, and the kynurenine-to-tryptophan ratio was increased. These findings suggest a role of increased inflammation and accumulation of neurotoxic metabolites in the pathogenesis of ICU delirium. Future studies should target this pathway to validate metabolites in the tryptophan pathway as risk biomarkers in patients with ICU delirium.

Relationship Between Pharmacy Students' Use of Self-Regulated Learning Strategies and Course Outcomes.

Objective. To determine the relationship between student-reported, self-regulated learning (SRL) with use of supplementary material, and overall performance in an advanced therapeutics course in a Doctor of Pharmacy program. Methods. A modified version of the Self-Regulated Strategy Inventory (SRSI-SI) was used to measure three distinct SRL factors: managing study behaviors, managing environment, and maladaptive regulatory behaviors. An instructor created a supplemental 36-question practice quiz and flashcard activity. The in-class assessment and the three SRL factors were analyzed using the practice quiz, and the association between overall course grade and score in each factor domain was determined by regression. Results. Two-hundred seven students (98%) completed the SRSI. One hundred fifty-eight (79%) students reported using the optional practice quiz and doing so was associated with significantly higher in-class quiz scores (8.2 vs 7.6 out of 10) and higher overall course grade (88.0% vs 85.3%). Students reporting use of the optional practice quiz were significantly less likely to report poor study behaviors, inability to manage study environment, and maladaptive study habits. Lower overall course grades were significantly associated with maladaptive study habits. Conclusion. A positive association was determined between use of instructor-created supplemental activities and in-class quiz scores, self-regulated study behaviors, and overall course performance. Maladaptive study habits were associated with a modest negative correlation with overall course grade. The results suggest that when instructors create optional supplementary activities and assessments, many of the students who would benefit the most from the use of these activities fail to utilize the opportunity for extra practice.

Use of Patient and Disease Characteristics as Predictive Indicators of Rituximab Infusion-Related Reactions in Adult Malignant Hematology Patients at an Academic Medical Center.

BACKGROUND: Identification of predictive indicators for rituximab infusion-related reactions (R-IRRs) may allow clinicians to modify treatment plans for patients at high risk of reaction to reduce incidence. Use of predictive indicators would significantly improve the patient experience, reduce hospital resource utilization, and decrease infusion chair time. PATIENTS AND METHODS: This retrospective, single-center, observational study evaluated 173 adult malignant hematology patients who received their first dose of rituximab inpatient between July 31, 2015 and July 31, 2018. Patients were excluded if they received prior rituximab, and/or induction chemotherapy, or were pregnant at the time of exposure. The primary outcome was the overall incidence of R-IRRs during the study period. The secondary outcomes were associations between specific patient and disease characteristics and R-IRRs. RESULTS: Of the 173 patients evaluated, 109 met inclusion criteria and 64 were excluded. The overall incidence of R-IRRs was 31 (28.4%) of 109. The following patient and disease characteristics were significantly associated with R-IRRs on univariate analysis: higher actual body weight (P = .04), diagnosis (P = .01), lower hemoglobin (P = .02), and bone marrow involvement (P = .001). In a confirmatory stepwise regression model, higher actual body weight (P = .01) and bone marrow involvement (P = .003) were positively associated with R-IRRs. CONCLUSION: Actual body weight and bone marrow involvement may be utilized as potential predictive indicators of R-IRRs. Further study is needed to validate these indicators and determine appropriate utilization in practice.

Metabolomic association between venous thromboembolism in critically ill trauma patients and kynurenine pathway of tryptophan metabolism.

OBJECTIVE: Incidence of venous thromboembolism (VTE) in critically ill patients remains unacceptably high despite widespread use of thromboprophylaxis. A systems biology approach may be useful in understanding disease pathology and predicting response to treatment. Metabolite profile under specific environmental conditions provides the closest link to phenotype, but the relationship between metabolomics and risk of VTE in critically ill patients is unknown. In this study, metabolomics signatures are compared in patients with and without VTE. DESIGN: Multicenter case-control study using prospectively collected data from the Inflammation and Host Response to Injury program, with pathway and in silico gene expression analyses. SETTING: Eight level 1 US trauma centers. PATIENTS: Critically ill adults with blunt trauma who developed VTE within the first 28 days of hospitalization compared to patients without VTE (N-VTE). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patients included in the study (n = 20 VTE, n = 20 N-VTE) were mean age of 34 years, injury severity score of 35, and VTE diagnosed a median of 10.5 days after admission. Global metabolomics revealed two kynurenine metabolites, N-formylkynurenine (AUC = 0.77; 95% CI: 0.59-0.89) and 5-hydroxy-N-formylkynurenine (AUC = 0.80; 95% CI:0.63-0.90) significantly discriminated VTE and N-VTE; ratio between N-formylkynurenine/5-hydroxy-N-formylkynurenine improved predictive power (AUC = 0.87; 95% CI: 0.74-0.95). In the pathway analysis, tryptophan was the only significant metabolic pathway including N-formylkynurenine and 5-hydroxy-N-formylkynurenine (p < 0.001), and 8 proteins directly or indirectly interacted with these metabolites in the interaction network analysis. Of the 8 genes tested in the in silico gene expression analyses, KYNU (p < 0.001), CCBL1 (p < 0.001), and CCBL2 (p = 0.001) were significantly different between VTE and N-VTE, controlling for age and sex. CONCLUSIONS: Two novel kynurenine metabolites in the tryptophan pathway associated with hospital-acquired VTE, and 3 candidate genes were identified via pathway and interaction network analyses. Future studies are warranted to validate these findings in diverse populations using a multi-omics approach.

Innovative Use of Novel Biomarkers to Improve the Safety of Renally Eliminated and Nephrotoxic Medications.

Over the last decade, the discovery of novel renal biomarkers and research on their use to improve medication effectiveness and safety has expanded considerably. Pharmacists are uniquely positioned to leverage this new technology for renal assessment to improve medication dosing and monitoring. Serum cystatin C is a relatively new, inexpensive, functional renal biomarker that responds more quickly to changing renal function than creatinine and is not meaningfully affected by age, sex, skeletal muscle mass, dietary intake, or deconditioning. Cystatin C has been proposed as an adjunct or alternative to creatinine for glomerular filtration rate assessment and estimation of drug clearance. Tissue inhibitor of metalloproteinase-2·insulin-like growth factor-binding protein 7 ([TIMP-2]·[IGFBP7]) is a composite of two damage biomarkers released into the urine at a checkpoint in mitosis when renal cells undergo stress or sense a future risk of damage. Concentrations of [TIMP-2]·[IGFBP7] increase before a rise in serum creatinine is evident, thus providing insightful information for evaluation in the context of other patient data to predict the risk for impending kidney injury. This article provides a brief overview of novel renal biomarkers being used as a mechanism to improve medication safety including a discussion of cystatin C, as part of drug-dosing algorithms and specifically for vancomycin dosing, and the use of [TIMP-2]·[IGFBP7] for risk prediction in acute kidney injury and drug-induced kidney disease. Select cases of clinical experience with novel renal biomarkers are outlined, and lessons learned and future applications are described.

Comparison of darbepoetin alfa and epoetin alfa in the management of anemia of critical illness.

STUDY OBJECTIVE: To compare the effectiveness of darbepoetin alfa with epoetin alfa (recombinant human erythropoietin [rHuEPO]) for achieving transfusion independence and increasing hemoglobin concentrations in critically ill patients. DESIGN: Retrospective, descriptive study. SETTING: Level I trauma center intensive care units. PATIENTS: Seventy-two patients who spent at least 3 days in the cardio-thoracic, medical, or surgery-trauma intensive care units and received at least one weekly dose of rHuEPO 40,000 units (33 patients) or darbepoetin alfa 100 microg (39 patients). MEASUREMENTS AND MAIN RESULTS: Number of rHuEPO and darbepoetin alfa doses, hemoglobin concentrations, and cumulative number of transfusions were recorded for up to 28 days after the first dose was given, and the data were statistically analyzed. Beginning a median of 10 days after the patients were admitted to the intensive care unit, they received a median of 3.5 doses of darbepoetin alfa or 4 doses of rHuEPO. Mean hemoglobin concentrations at which treatment with darbepoetin alfa and rHuEPO were started were 8 and 8.2 g/dl, respectively (p=0.41). Transfusion independence was achieved in 44% of patients in the darbepoetin alfa group compared with 36% of patients in the rHuEPO group (p=0.63). Patients in both groups received a mean of 2.7 units of packed red blood cells during the 28-day study period. The mean change in hemoglobin levels from baseline over time did not significantly differ between groups (p=0.75). CONCLUSIONS: Patients receiving darbepoetin alfa 100 microg/week and those receiving rHuEPO 40,000 units/week for anemia of critical illness achieved similar rates of transfusion independence and increases in hemoglobin concentrations from baseline at 28 days. Compared with previously published studies, erythropoietic agents were administered late in the course of critical illness in response to low hemoglobin concentrations.

Trends in utilization of warfarin and direct oral anticoagulants in older adult patients with atrial fibrillation.

PURPOSE: Results of a study to determine trends in oral anticoagulant (OAC) use and OAC switching in patients with atrial fibrillation (AF) or atrial flutter are presented. METHODS: Warfarin has been the most prescribed anticoagulant in patients with AF for decades. Since 2010, several direct OACs (DOACs) have gained U.S. marketing approval for stroke prevention in AF or atrial flutter. A cross-sectional longitudinal analysis was conducted using healthcare and prescription claims databases to characterize OAC use and rates of OAC and DOAC switching during the period 2008-14 in cohorts of Medicare beneficiaries 65 years of age or older with AF or atrial flutter. RESULTS: Overall, 66% of patients with AF or atrial flutter were receiving OACs during the study period. The prevalence of warfarin use decreased from 69.8% in 2008 to 42.2% in 2014. This decrease in warfarin use was paralleled by an increase in dabigatran use, which rose from 1.3% in 2010 to 12.1% in 2011 and then declined to 7.6% in 2014. The prevalence of rivaroxaban use increased from 0.13% in 2011 to 13.87% in 2014. Among anticoagulated patients, an average of 6% annually were switched from one OAC to another. CONCLUSION: Overall OAC utilization in patients with AF or atrial flutter remained steady over the study period. Beginning in 2010, a gradual decrease in use of warfarin was paralleled by an increase in use of DOACs.

No difference in mechanical ventilation-free hours in critically ill patients who received intravenous, oral, or enteral phosphate replacement.

PURPOSE: To determine the impact on duration of mechanical ventilation (MV) and the need for reintubation after changing from intravenous (IV) to oral phosphate formulations, in response to a national shortage of IV phosphate. METHODS: A retrospective study was performed in adult patients who required MV for at least 48 hours. RESULTS: A total of 136 patients were included, with 68 patients in both the restricted phosphate group and unrestricted phosphate groups. There was no difference in the cumulative phosphate supplementation received (IV and oral) between groups (P=.08). The overall mean serum phosphorus concentration in unrestricted vs restricted group was 3.0 vs 2.9 mg/dL, respectively (P=.24), and the phosphorus concentration was not significantly different between groups during the first 21 days of the study (P=.24). The median MV-free hours in the unrestricted group was 462 hours compared with 507 hours in the restricted group (P=.16), and 9 (13.2%) of patients in each group required reintubation (P=.99). There was no significant difference in mortality, or hospital, or intensive care unit (ICU) length of stay. CONCLUSIONS: No difference in MV-free hours or need for reintubation was observed after a national shortage requiring the restriction of IV phosphate supplementation. Oral phosphate replacement is a safe and an efficient alternative.