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Purpose: To examine the effectiveness and safety of single-isocenter multitarget stereotactic radiosurgery using a volume-adapted dosing strategy in patients with 4 to 10 brain metastases. Methods and Materials: Adult patients with 4 to 10 brain metastases were eligible for this prospective trial. The primary endpoint was overall survival. Secondary endpoints were local recurrence, distant brain failure, neurologic death, and rate of adverse events. Exploratory objectives were neurocognition, quality of life, dosimetric data, salvage rate, and radionecrosis. Dose was prescribed in a single fraction per RTOG 90-05 or as 5 Gy × 5 fractions for lesions ≥3 cm diameter, lesions involving critical structures, or single-fraction brain V12Gy >20 mL. Results: Forty patients were treated with median age of 61 years, Karnofsky performance status 90, and 6 brain metastases. Twenty-two patients survived longer than expected from the time of protocol SRS, with 1 living patient who has not reached that milestone. Median overall survival was 8.1 months with a 1-year overall survival of 35.7%. The 1-year local recurrence rate was 5% (10 of 204 of evaluable lesions) in 12.5% (4 of 32) of the patients. Distant brain failure was observed in 19 of 32 patients with a 1-year rate of 35.8%. Grade 1-2 headache was the most common complaint, with no grade 3-5 treatment-related adverse events. Radionecrosis was observed in only 5 lesions, with a 1-year rate of 1.5%. Rate of neurologic death was 20%. Neurocognition and quality of life did not significantly change 3 months after SRS compared with pretreatment. Conclusions: These results suggest that volume-adapted dosing single-isocenter multitarget stereotactic radiosurgery is an effective and safe treatment for patients with 4 to 10 brain metastases.

Objective: Common data models provide a standard means of describing data for artificial intelligence (AI) applications, but this process has never been undertaken for medications used in the intensive care unit (ICU). We sought to develop a common data model (CDM) for ICU medications to standardize the medication features needed to support future ICU AI efforts., Materials and Methods: A 9-member, multi-professional team of ICU clinicians and AI experts conducted a 5-round modified Delphi process employing conference calls, web-based communication, and electronic surveys to define the most important medication features for AI efforts. Candidate ICU medication features were generated through group discussion and then independently scored by each team member based on relevance to ICU clinical decision-making and feasibility for collection and coding. A key consideration was to ensure the final ontology both distinguished unique medications and met Findable, Accessible, Interoperable, and Reusable (FAIR) guiding principles., Results: Using a list of 889 ICU medications, the team initially generated 106 different medication features, and 71 were ranked as being core features for the CDM. Through this process, 106 medication features were assigned to 2 key feature domains: drug product-related (n = 43) and clinical practice-related (n = 63). Each feature included a standardized definition and suggested response values housed in the electronic data library. This CDM for ICU medications is available online., Conclusion: The CDM for ICU medications represents an important first step for the research community focused on exploring how AI can improve patient outcomes and will require ongoing engagement and refinement., Competing Interests: The authors have no competing interests to disclose., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Medical Informatics Association.)

Objectives: To summarize the effectiveness of implementation strategies for ICU execution of recommendations from the 2013 Pain, Agitation/Sedation, Delirium (PAD) or 2018 PAD, Immobility, Sleep Disruption (PADIS) guidelines., Data Sources: PubMed, CINAHL, Scopus, and Web of Science were searched from January 2012 to August 2023. The protocol was registered with PROSPERO (CRD42020175268)., Study Selection: Articles were included if: 1) design was randomized or cohort, 2) adult population evaluated, 3) employed recommendations from greater than or equal to two PAD/PADIS domains, and 4) evaluated greater than or equal to 1 of the following outcome(s): short-term mortality, delirium occurrence, mechanical ventilation (MV) duration, or ICU length of stay (LOS)., Data Extraction: Two authors independently reviewed articles for eligibility, number of PAD/PADIS domains, quality according to National Heart, Lung, and Blood Institute assessment tools, implementation strategy use (including Assess, prevent, and manage pain; Both SAT and SBT; Choice of analgesia and sedation; Delirium: assess, prevent, and manage; Early mobility and exercise; Family engagement and empowerment [ABCDEF] bundle) by Cochrane Effective Practice and Organization of Care (EPOC) category, and clinical outcomes. Certainty of evidence was assessed using Grading of Recommendations Assessment, Development, and Evaluation., Data Synthesis: Among the 25 of 243 (10.3%) full-text articles included ( n = 23,215 patients), risk of bias was high in 13 (52%). Most studies were cohort ( n = 22, 88%). A median of 5 (interquartile range [IQR] 4-7) EPOC strategies were used to implement recommendations from two (IQR 2-3) PAD/PADIS domains. Cohort and randomized studies were pooled separately. In the cohort studies, use of EPOC strategies was not associated with a change in mortality (risk ratio [RR] 1.01; 95% CI, 0.9-1.12), or delirium (RR 0.92; 95% CI, 0.82-1.03), but was associated with a reduction in MV duration (weighted mean difference [WMD] -0.84 d; 95% CI, -1.25 to -0.43) and ICU LOS (WMD -0.77 d; 95% CI, -1.51 to 0.04). For randomized studies, EPOC strategy use was associated with reduced mortality and MV duration but not delirium or ICU LOS., Conclusions: Using multiple implementation strategies to adopt PAD/PADIS guideline recommendations may reduce mortality, duration of MV, and ICU LOS. Further prospective, controlled studies are needed to identify the most effective strategies to implement PAD/PADIS recommendations., Competing Interests: Dr. Devlin disclosed he has received research funding from BioExcel, Sedana Medical, and the National Institute of Aging (R13185760, R33HL23452, and R21/R33 AG05797) and that he serves as a consultant to BioExcel, La Jolla Pharmaceuticals, and Ceribell. Dr. Kane-Gill received funding from the Society of Critical Care Medicine. The remaining authors have disclosed that they do not have any potential conflict of interest., (Copyright © 2024 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Background: Concurrent administration of vancomycin and piperacillin/tazobactam (VAN+PTZ) may increase the risk of acute kidney injury (AKI) in hospitalized patients. Comprehensive characterization of VAN+PTZ associated AKI and recovery patterns remains lacking in previous reports. Objective: To compare the incidence of AKI associated with VAN+PTZ compared to either cefepime (CEF) or meropenem (MER) with VAN in adult general ward patients. Methods: A multicenter, retrospective, propensity score cohort study was conducted in non-critically ill adult patients. Included patients were concurrently administered VAN+PTZ or VAN+CEF/MER. Patients developing AKI ≤48 hours following combination therapy were excluded. The primary endpoint was to compare the incidence of AKI between study groups. Multivariable Cox regression modeling in predicting AKI was also conducted. Results: A total of 3199 patients met inclusion criteria and were evaluated. The incidence of AKI in VAN+PTZ and VAN+CEF/MER groups were 16.4% and 8.7%, respectively ( P < .001). The onset to AKI was 1.8 days earlier with VAN+PTZ compared to VAN+CEF/MER ( P < .001). Multivariable prediction model showed concomitant VAN+PTZ was identified as an independent risk factor of developing AKI (HR 2.34, 1.82-3.01, P < .001). The VAN+PTZ group experienced significantly higher rates of severe AKI (stage II or III) compared to the VAN+CEF/MER group ( P = .002). No differences in the AKI recovery patterns were found between study groups. Conclusions: Concomitant VAN+PTZ in adult general ward patients was independently associated with an increased risk of AKI overall. More severe AKI was also associated with VAN+PTZ., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Fluid overload, while common in the ICU and associated with serious sequelae, is hard to predict and may be influenced by ICU medication use. Machine learning (ML) approaches may offer advantages over traditional regression techniques to predict it. We compared the ability of traditional regression techniques and different ML-based modeling approaches to identify clinically meaningful fluid overload predictors. This was a retrospective, observational cohort study of adult patients admitted to an ICU ≥ 72 h between 10/1/2015 and 10/31/2020 with available fluid balance data. Models to predict fluid overload (a positive fluid balance ≥ 10% of the admission body weight) in the 48-72 h after ICU admission were created. Potential patient and medication fluid overload predictor variables (n = 28) were collected at either baseline or 24 h after ICU admission. The optimal traditional logistic regression model was created using backward selection. Supervised, classification-based ML models were trained and optimized, including a meta-modeling approach. Area under the receiver operating characteristic (AUROC), positive predictive value (PPV), and negative predictive value (NPV) were compared between the traditional and ML fluid prediction models. A total of 49 of the 391 (12.5%) patients developed fluid overload. Among the ML models, the XGBoost model had the highest performance (AUROC 0.78, PPV 0.27, NPV 0.94) for fluid overload prediction. The XGBoost model performed similarly to the final traditional logistic regression model (AUROC 0.70; PPV 0.20, NPV 0.94). Feature importance analysis revealed severity of illness scores and medication-related data were the most important predictors of fluid overload. In the context of our study, ML and traditional models appear to perform similarly to predict fluid overload in the ICU. Baseline severity of illness and ICU medication regimen complexity are important predictors of fluid overload., (© 2023. The Author(s).)

Background: The clinical utility of methicillin-resistant Staphylococcus aureus (MRSA) nasal screening appears promising for antimicrobial stewardship programs. However, a paucity of data remains on the diagnostic performance of culture-based MRSA screen in the intensive care unit (ICU) for pneumonia and bacteremia., Objective: The objective of this study was to compare the predictive value of culture-based MRSA nasal screening for pneumonia and bacteremia in ICU and general ward patients., Methods: This multicenter, retrospective study was conducted over a 23-month period. Adult patients with MRSA nasal screening ≤48 hours of collecting a respiratory and/or blood culture with concurrent initiation of anti-MRSA therapy were included. The primary endpoint was to compare the negative predictive value (NPV) associated with culture-based MRSA nasal screening between ICU and general ward patients with suspected pneumonia., Results: A total of 5106 patients representing the ICU (n = 2515) and general ward (n = 2591) were evaluated. The NPV of the MRSA nares for suspected pneumonia was not significantly different between ICU and general ward patient populations (98.3% and 97.6%, respectively; P = 0.41). The MRSA nares screening tool also had a high NPV for suspected bacteremia in ICU (99.8%) and general ward groups (99.7%) ( P = 0.56). The overall positive MRSA nares rates in the ICU and general ward patient populations were 9.1% and 8.2%, respectively ( P = 0.283). Moreover, MRSA-positive respiratory and blood cultures among ICU patients were 5.8% and 0.8%, respectively., Conclusion and Relevance: Our findings support the routine use of MRSA nasal screening using the culture-based method in ICU patients with pneumonia. Further research on the clinical performance for MRSA bacteremia in the ICU is warranted.

Study Objective: Severe coronavirus disease 2019 (COVID-19) increases the risk of thrombotic complications with unfractionated heparin (UFH) as a commonly used agent in managing venous thromboembolism (VTE). The optimal anticoagulation intensity and monitoring parameters in intensive care unit (ICU) COVID-19 patients remains controversial. The primary study aim was to evaluate the relationship between anti-Xa and thromboelastography (TEG) reaction (R) time in patients with severe COVID-19 receiving therapeutic UFH infusions., Design: Single-center, retrospective study conducted over a 15-month period (2020-2021)., Setting: Academic medical center (Banner University Medical Center Phoenix)., Patients: Adult patients with severe COVID-19 administered therapeutic UFH infusions with one or more corresponding TEG, and anti-Xa assessments drawn within ≤2 hours of each other were included. The primary end point was the correlation between anti-Xa and TEG R time. Secondary aims were to describe the correlation between activated partial thromboplastin time (aPTT) and TEG R time, as well as clinical outcomes. Pearson's coefficient was used to evaluate the correlation using a kappa measure of agreement., (© 2023 Pharmacotherapy Publications, Inc.)

While medication regimen complexity, as measured by a novel medication regimen complexity-intensive care unit (MRC-ICU) score, correlates with baseline severity of illness and mortality, whether the MRC-ICU improves hospital mortality prediction is not known. After characterizing the association between MRC-ICU, severity of illness and hospital mortality we sought to evaluate the incremental benefit of adding MRC-ICU to illness severity-based hospital mortality prediction models. This was a single-center, observational cohort study of adult intensive care units (ICUs). A random sample of 991 adults admitted ≥ 24 h to the ICU from 10/2015 to 10/2020 were included. The logistic regression models for the primary outcome of mortality were assessed via area under the receiver operating characteristic (AUROC). Medication regimen complexity was evaluated daily using the MRC-ICU. This previously validated index is a weighted summation of medications prescribed in the first 24 h of ICU stay [e.g., a patient prescribed insulin (1 point) and vancomycin (3 points) has a MRC-ICU = 4 points]. Baseline demographic features (e.g., age, sex, ICU type) were collected and severity of illness (based on worst values within the first 24 h of ICU admission) was characterized using both the Acute Physiology and Chronic Health Evaluation (APACHE II) and the Sequential Organ Failure Assessment (SOFA) score. Univariate analysis of 991 patients revealed every one-point increase in the average 24-h MRC-ICU score was associated with a 5% increase in hospital mortality [Odds Ratio (OR) 1.05, 95% confidence interval 1.02-1.08, p = 0.002]. The model including MRC-ICU, APACHE II and SOFA had a AUROC for mortality of 0.81 whereas the model including only APACHE-II and SOFA had a AUROC for mortality of 0.76. Medication regimen complexity is associated with increased hospital mortality. A prediction model including medication regimen complexity only modestly improves hospital mortality prediction., (© 2023. The Author(s).)

Study Objective: Thromboelastography (TEG) offers a more dynamic assessment of hemostasis over activated partial thromboplastin time (aPTT). However, the clinical utility of TEG in monitoring bivalirudin during extracorporeal membrane oxygenation (ECMO) remains unknown. The purpose of this study was to evaluate the correlation between aPTT and TEG in adult ECMO patients anticoagulated with bivalirudin., Design: Multicenter, retrospective, cohort study conducted over a 2-year period., Setting: Two academic university medical centers (Banner University Medical Center) in Phoenix and Tucson, AZ., Patients: Adult patients requiring ECMO and bivalirudin therapy with ≥1 corresponding standard TEG and aPTT plasma samples drawn ≤4 h of each other were included. The primary endpoint was to determine the correlation coefficient between the standard TEG reaction (R) time and bivalirudin aPTT serum concentrations., Measurements and Main Results: A total of 104 patients consisting of 848 concurrent laboratory assessments of R time and aPTT were included. A moderate correlation between TEG R time and aPTT was demonstrated in the study population (r = 0.41; p < 0.001). Overall, 502 (59.2%) concurrent assessments of TEG R time and aPTT values showed agreement on whether they were sub-, supra-, or therapeutic according to the institution's classification for bivalirudin. The 42.2% (n = 271/642) discordant TEG R times among "therapeutic" aPTT were almost equally distributed between subtherapeutic and supratherapeutic categories., Conclusions: Moderate correlation was found between TEG R time and aPTT associated with bivalirudin during ECMO in critically ill adults. Further research is warranted to address the optimal test to guide clinical decision-making for anticoagulation dosing in ECMO patients., (© 2023 Pharmacotherapy Publications, Inc.)

Purpose: Inhaled epoprostenol (iEPO) is a viable, temporizing option for acute respiratory distress syndrome (ARDS), although the optimal iEPO dosing strategy remains inconclusive. The purpose of this study was to evaluate oxygenation and ventilation parameters in a comparison of weight-based and fixed-dose iEPO in adult patients with moderate-to-severe ARDS., Methods: A retrospective cohort study was conducted at 2 academic medical centers in adult intensive care unit (ICU) patients administered either fixed-dose or weight-based iEPO for moderate-to-severe ARDS. The primary endpoint was the highest recorded change in the ratio of arterial oxygen partial pressure to fractional inspired oxygen (PaO2/FiO2) within 4 hours of baseline. Secondary analyses compared responder rates within 4 hours of initiation, oxygenation and ventilation parameters, in-hospital mortality rates, mechanical ventilation duration, length of stay (ICU and hospital), and tracheostomy rates between the study groups., Results: A total of 294 patients were included, n = 194 with 100 (34.0%) and 194 (66.0%) in the weight-based and fixed-dose iEPO groups, respectively. The mean (SD) change in the highest recorded PaO2/FiO2 value from baseline up to 4 hours after initiation in the fixed-dose and weight-based groups was 81.1 (106.0) and 41.0 (72.5) mm Hg, respectively (P = 0.0015). The responder rate at 4 hours after iEPO initiation was significantly higher in the fixed-dose group (69.9%) than in the weight-based group (30.1%) (P = 0.02). The only predictor of response was fixed-dose administration (odds ratio, 3.28; 95% confidence interval, 1.6-6.7; P = 0.0012). Clinical outcomes were comparable between the groups., Conclusion: Fixed-dose iEPO was associated with significantly higher response rates then weight-based iEPO during the first 4 hours of therapy. Fixed-dose iEPO is a more convenient strategy than weight-based approaches., (© American Society of Health-System Pharmacists 2022. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: The risk of acute kidney injury (AKI) associated with concomitant vancomycin and piperacillin/tazobactam in the intensive care unit (ICU) remains controversial. The aim of this study was to compare the AKI incidence associated with concomitant vancomycin and piperacillin/tazobactam compared to either cefepime or meropenem with vancomycin in the ICU., Materials and Methods: A multicenter, retrospective, propensity score-matched cohort study was conducted in adult ICU patients administered vancomycin in combination with either piperacillin/tazobactam, cefepime, or meropenem were included. Patients developing AKI ≤48 h following combination therapy initiation were excluded. The primary endpoint was to compare the incidence of AKI associated with concomitant antimicrobial therapy. Multivariable Cox regression modeling in predicting AKI was also conducted., Results: A total of 1044 patients were matched. The AKI incidence in vancomycin- piperacillin/tazobactam and vancomycin-cefepime/meropenem groups were 21.9% and 16.8%, respectively (p = 0.068). Multivariable prediction models showed concomitant vancomycin-piperacillin/tazobactam was an independent risk factor of AKI using serum creatinine only (HR 1.52, 1.10-2.10, p = 0.011) and serum creatinine with urine output-based KDIGO criteria (HR 1.77, 1.18-2.67, p = 0.006). No significant differences between groups were observed for AKI recovery patterns or mortality., Conclusion: Concomitant vancomycin and piperacillin/tazobactam administration in adult ICU patients was independently associated with an increased risk of AKI., Competing Interests: Declaration of Competing Interest The authors(s) declare(s) that there is no conflict of interest., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objectives: Clinicians learn from prior adverse events through pharmacovigilance allowing for improved medication safety in the medication use process; therefore, adverse drug reaction (ADR) reporting needs to be maximized. This systematic review was conducted to determine whether engaging patients/caregivers in ADR reporting during a patient's hospitalization provides further information about ADRs not obtained from traditional sources of reporting (i.e., voluntary reporting, medical record review)., Methods: This review was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. A literature search was conducted from January 2018 to June 2019 in PubMed, CINAHL, and Embase. Studies were included if they were (i) conducted in the inpatient setting, (ii) surveyed patients/caregivers, (iii) compared patient/caregiver reporting with another source of reporting, and (iv) evaluated ADRs. Studies completed in an outpatient setting or nursing home were excluded., Results: A total of 11 studies were included. Sources of ADR information from patient/caregiver were obtained through interviews, surveys, questionnaires, or open-ended responses. Patient reporting was compared with medical record reports (7 articles) and health care professional reporting (4 articles). Approximately 11% to 35% of ADRs reported from patients were not identified through voluntary reporting by health care professionals, and 5.6% to 66% of ADRs obtained from patient reporting were not provided in the medical record., Conclusions: Patients/caregivers are important sources of safety information to improve system and practice of medication use that may not be recorded by other surveillance methods. Administrators and clinicians need to determine the best approach to integrate patients/caregivers into routine reporting for optimal engagement., Competing Interests: The authors disclose no conflict of interest and no sources of support., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Among gynecologic malignancies, ovarian cancer (OC) has the poorest survival rate, and its clinical management remains challenging due to the high rate of recurrence and chemoresistance. Improving survival for these patients is critical, although this requires the ability to translate preclinical studies to actual patient care: bench to bedside and back. Our objective was to develop a preclinical model that accurately represents tumor biology and its microenvironment. We utilized SKOV-3, OVCAR-8, and CS-99 cell lines to show that this model was suitable for in vitro assessment of cell proliferation. We tested OC cells independently and in co-culture with cancer associated fibroblasts (CAFs) or immune cells. Additionally, we used patient-derived ovarian carcinoma and carcinosarcoma samples to show that the system maintains the histologic morphology of the primary tissue after 7 days. Moreover, we tested the response to chemotherapy using both cell lines and patient-derived tumor specimens and confirmed that cell death was significantly higher in the treated group compared to the vehicle group. Finally, we immune profiled the 3-D model containing patient tissue after several days in the bioreactor system and revealed that the immune populations are still present. Our data suggest that this model is a suitable preclinical model to aid in research that will ultimately impact the treatment of patients with gynecologic cancer., Competing Interests: Declaration of conflicting interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: R.C.A. has participated in Advisory Boards for Leap Therapeutics, AstraZeneca, GSK, Merck, VBL Therapeutics, and Caris Life Sciences. M.J.B. serves as an advisory board member for AstraZeneca, Clovis, and GSK. The remaining authors declare no conflict of interest., (© The Author(s) 2021.)

Background: Vancomycin therapeutic drug monitoring is routinely performed but the specific measure used in practice is variable., Objective: To evaluate the relationship between the first measured vancomycin trough, area-under-the-curve (AUC), and failure in patients with MRSA bacteremia., Methods: This retrospective, cohort study included adult non-neutropenic patients with MRSA bacteremia who received vancomycin. The primary outcome was treatment failure. Initial trough and AUC values were compared between the failure and success groups. Classification and regression tree analysis was used to identify thresholds associated with failure. Multivariate analysis was performed to control for identified confounders., Results: There were 89 patients. Failure occurred in 23 (26%). Trough and AUC values associated with failure were < 10.6 mg/L (39% vs. 13%; P = 0.006) and AUC < 410mg*h/L (40% vs. 17%; P = 0.014). Both remained significant after controlling covariates (trough < 10.6 mg/L, OR [95% CI] = 4.91 [1.6-15]; AUC<410mg*h/L, OR [95% CI] = 3.13 [1.14-8.62]). Only AUC was predictive of nephrotoxicity., Conclusion: Failure was more common with troughs < 10.6 mg/L or AUC < 410 mg*h/L. Supratherapeutic AUCs, but not trough, were associated with nephrotoxicity., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Agitation and delirium are common in mechanically ventilated adult intensive care unit (ICU) patients and may contribute to delayed extubation times. Difficult-to-wean ICU patients have been associated with an increased risk of longer ICU length of stays and mortality. The purpose of this systematic review and meta-analysis is to evaluate the evidence of dexmedetomidine facilitating successful mechanical ventilation extubation in difficult-to-wean ICU patients and clinical outcomes., Methods: A literature search was conducted using MEDLINE, EMBASE, PsycINFO, Cumulative Index to Nursing and Allied Health Literature, Global Health, Cochrane Central Register of Controlled Trials, Clinical Trial Registries, and the Health Technology Assessment Database from inception to December 5, 2019. Randomized controlled trials evaluating dexmedetomidine with the intended purpose to facilitate mechanical ventilation liberation in adult ICU patients (≥18 years) experiencing extubation failure were included. The primary outcome of time to extubation was evaluated using the weighted mean difference (WMD), with a random effects model. Secondary analyses included hospital and ICU length of stay, in-hospital mortality, hypotension, and bradycardia., Results: A total of 6 trials (n = 306 patients) were included. Dexmedetomidine significantly reduced the time to extubation (WMD: -11.61 hours, 95% CI: -16.5 to -6.7, P = .005) and ICU length of stay (WMD: -3.04 days; 95% CI: -4.66 to -1.43). Hypotension risk was increased with dexmedetomidine (risk ratio [RR]: 1.62, 95% CI: 1.05-2.51), but there was no difference in bradycardia risk (RR: 3.98, 95% CI: 0.70-22.78). No differences were observed in mortality rates (RR: 1.30, 95% CI: 0.45-3.75) or hospital length of stay (WMD: -2.67 days; 95% CI: -7.73 to 2.39)., Conclusions: Dexmedetomidine was associated with a significant reduction in the time to extubation and shorter ICU stay in difficult-to-wean ICU patients. Although hypotension risk was increased with dexmedetomidine, no differences in other clinical outcomes were observed.

Purpose: Several reports have demonstrated similar effects on oxygenation between inhaled epoprostenol (iEPO) compared to inhaled nitric oxide (iNO) for acute respiratory distress syndrome (ARDS). Previous studies directly comparing oxygenation and clinical outcomes between iEPO and iNO exclusively in an adult ARDS patient population utilized a weight-based dosing strategy. The purpose of this study was to compare the clinical and economic impact between iNO and fixed-dosed iEPO for ARDS in adult intensive care unit (ICU) patients., Methods: This retrospective cohort study was conducted at a major academic medical center between January 1, 2014, and October 31, 2018. Patients ≥18 years of age with moderate-to-severe ARDS were included. The primary end point was to compare the mean change in partial arterial oxygen pressure to fraction of inspired oxygen (Pao 2 : Fio 2 ) at 4 hours from baseline between iEPO and iNO. Other secondary aims were total acquisition drug costs, in-hospital mortality, ICU and hospital length of stay, and duration of mechanical ventilation., Results: A total of 239 patients were included with 139 (58.2%) and 100 (41.8%) in the iEPO and iNO groups, respectively. The mean change in Pao 2 : Fio 2 at 4 hours from baseline in the iEPO and iNO groups were 31.4 ± 54.6 and 32.4 ± 42.7 mm Hg, respectively ( P = .88). The responder rate at 4 hours was similar between iEPO and iNO groups (64.7% and 66.0%, respectively, P = .84). Clinical outcomes including mortality, overall hospital and ICU length of stay, and mechanical ventilation duration were similar between iEPO and iNO groups. Estimated annual cost-savings realized with iEPO was USD1 074 433., Conclusion: Fixed-dose iEPO was comparable to iNO in patients with moderate-to-severe ARDS for oxygenation and ventilation parameters as well as clinical outcomes. Significant cost-savings were realized with iEPO use.

Background: Inappropriate albumin use in clinical practice remains problematic. Health-systems face continued challenges in promoting cost-appropriate use., Objective: To evaluate the clinical and economic impact of a clinical pharmacist-led intervention strategy targeting inappropriate albumin use in general ward patients., Methods: A retrospective cohort study evaluated all adult (≥18 years) general ward patients administered ≥1 dose of albumin at a university medical center over a 2-year period. The intervention consisted of a clinical pharmacist-led strategy intervening on all albumin orders not in accordance with institutional guidelines. The primary end point was to compare inappropriate albumin utilization before and after implementation. Secondary end points compared the rates of inappropriate albumin use adjusted for hospital admission and patient-days as well as associated costs by appropriateness between study periods., Results: A total of 4420 patients were screened, with 1971 (44.6%) patients meeting inclusion criteria. The clinical pharmacist strategy significantly reduced inappropriate albumin (grams) utilization by 86.0% ( P < 0.001). A 7-fold reduction of inappropriate albumin administered adjusted for the number of patient admissions was found from the preimplementation period following clinical pharmacist intervention strategy implementation (415.3 ± 83.2 vs 57.5 ± 34.2 g per 100 general ward hospital admissions, respectively; P < 0.001). Also, the adjusted inappropriate albumin rate was reduced from 62.2 ± 12.3 to 8.6 ± 5.2 g per 100 patient-days in the preimplementation and postimplementation periods, respectively ( P < 0.001). Annual cost savings were $421 455 overall, with $341 930 resulting from mitigation of inappropriate use., Conclusion and Relevance: Clinical pharmacist-led interventions significantly reduced inappropriate albumin use and costs in hospitalized patients.

Purpose: Nonbenzodiazepines are preferred for continuous sedation in mechanically ventilated intensive care unit (ICU) patients. Although dexmedetomidine and propofol have blood pressure lowering properties, limited data exist about the hemodynamic effects of concomitant administration. The purpose of this study was to compare the adverse hemodynamic event rate with concomitant dexmedetomidine and propofol compared to either agent alone in mechanically ventilated ICU patients., Methods: This retrospective cohort study was conducted at a university medical center. Adult ICU patients (≥18 years) admitted between October 20, 2015, and January 25, 2018, and administered concurrent dexmedetomidine and propofol or either agent alone for ≥24 hours were included. Mean arterial pressure, heart rate, and sedative dosing requirements were assessed from initiation to 72 hours after initiation. The primary end point was comparing the incidence of hypotension among study groups. Secondary aims compared the incidence of tachycardia and bradycardia as well as clinical outcomes., Results: Overall, 276 patients were included among combination (n = 93), dexmedetomidine (n = 91), and propofol (n = 92) groups. The incidence of hypotension was significantly higher in patients administered concomitant dexmedetomidine and propofol (62.4%) compared to those administered dexmedetomidine (23.1%) or propofol (23.9%) alone ( P < .0001). Adjunctive dexmedetomidine with propofol was also associated with higher rates of clinically relevant hypotension requiring treatment ( P = .048). The tachycardia incidence in the concomitant, dexmedetomidine, and propofol groups were 30.1%, 28.6%, and 14.1%, respectively ( P = 02). Only 1.4% (n = 4) of all study patients developed bradycardia. Concomitant therapy was an independent risk factor of hypotension compared to either dexmedetomidine (odds ratio [OR]: 6.7, 95% confidence interval [CI]: 2.61-17.3, P < .0001) or propofol (OR: 2.89, 95% CI: 1.24-6.74, P = .014) monotherapy. Patients experiencing hypotension were associated with worse clinical outcomes., Conclusion: Concomitant dexmedetomidine and propofol use in mechanically ventilated patients increased the risk of hypotensive events. Adjunctive dexmedetomidine with propofol administration in the critically ill warrants caution.

Purpose: Stress ulcer prophylaxis (SUP) is routinely administered to critically ill patients for the prevention of stress ulcer-induced, clinically important bleeding (CIB). Recently, the value of SUP has been questioned due to the perceived decline in CIB and the potential for infectious complications secondary to acid suppressive therapy. The SUP-ICU trial is a large, randomized controlled trial comparing intravenous pantoprazole with placebo for the indication of SUP. It is hoped that this trial would answer many of the questions pertaining to the overall value of SUP. This article will provide an in-depth assessment of the SUP-ICU trial in the context of the overall body of literature in this area. Furthermore, applications for clinical practice and recommendations on the provision of SUP are provided. Summary: The SUP-ICU trial revealed no difference in the primary outcome of 90-day mortality with pantoprazole but lower rates of CIB were noted (which was a secondary outcome). Overall, these data provide important insight into the value of SUP along with other questions related to the provision of SUP such as the relationship between CIB and mortality, infectious complications, and enteral nutrition. Conclusions: The SUP-ICU trial is a landmark trial describing the value of SUP in a modern-day setting of intensive care unit (ICU) practice. The provision of SUP should be continued in high-risk patients. Future studies are ongoing that will add further insight to this routine practice., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2019.)

Purpose: The purpose of this study was to compare the volume of fluid removal associated with and without 25% albumin administration in conjunction with hemodialysis. Methods: This retrospective, cohort study was conducted at a large academic medical center over a 6-month period to compare the net fluid amount removed (mL) during hemodialysis between patients administered 25% albumin and those without albumin. Results: A total of 238 patients consisting of 973 unique hemodialysis sessions were evaluated. The mean overall net fluid removed by hemodialysis in the 25% albumin and no albumin groups were 1242 mL and 1899 mL, P < .001, respectively. No albumin group had significantly higher mean fluid losses compared with 25% albumin for a total dose of either 25 g ( P = .001) or 50 g ( P = .001). There were no significant differences in mean fluid loss between the no albumin group and patients receiving 75 g or 100 g of albumin. Post hoc analysis failed to demonstrate a dose-dependent response in those patients receiving 25% albumin and no albumin. Conclusion: Hyperoncotic albumin administered during hemodialysis sessions reduced net fluid loss associated with hemodialysis. The findings of this study do not support the routine use of 25% albumin to improve fluid removal during dialysis., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2019.)

Background: Optimal albumin use in the intensive care unit (ICU) remains challenging with inappropriate use approaching 50%. No published reports have described clinical pharmacist impact aimed at mitigating inappropriate albumin use in the ICU. Objective: To evaluate the clinical and economic impact of a clinical pharmacist-led intervention strategy targeting inappropriate albumin in the ICU. Methods: A retrospective cohort study evaluated all adult (≥18 years) ICU patients administered albumin at an academic medical center over a 2-year period. Institutional guidelines were developed with clinical pharmacists targeting inappropriate albumin use. The primary end point was to compare inappropriate use of albumin administered before and after pharmacist intervention implementation. Secondary analyses compared the overall albumin use between study periods. In-hospital mortality, length of stay, and albumin-related costs between study periods were also compared. Results: A total of 4419 patients were identified, with 2448 (55.4%) critically ill patients included. The pharmacist-led strategy resulted in a 50.9% reduction of inappropriate albumin use ( P < 0.001). The rate of inappropriate albumin use was 44.3 ± 10.5 and 5.5 ± 2.9 g per patient-day in the preimplementation and postimplementation periods, respectively ( P < 0.001). Costs associated with overall and inappropriate albumin use in the ICU decreased by 34.8% and 87.1%, respectively. Total annual cost-savings was $355 393 in the ICUs. No differences in clinical outcomes were found. Conclusion and Relevance: Clinical pharmacist-led interventions reduced overall and inappropriate albumin use and costs without negatively affecting clinical outcomes.

Introduction: There is an increased risk of potential drug-drug interactions (pDDIs) in critically ill patients based on the number of drugs received. The occurrence of pDDIs and clinical significance is not well described., Objective: The aim was to provide insight into important clinical issues and offer guidance on drug-drug interaction (DDI) surveillance through the performance of a systematic review., Methods: Five targeted objectives were developed, a priori, which guided study selection and data abstraction. Two independent reviewers extracted the definition, frequency, type, and clinical significance of pDDIs. A meta-analysis was performed to evaluate the proportion of patients exposed to a pDDI. Three data sources (PubMed, Embase, and Scopus) were utilized for the search to include studies that evaluated pDDIs in adult critically ill patients. Included studies in the systematic review and meta-analysis were required to be full text., Results: A total of 39 studies met inclusion criteria. Definitions of pDDIs were diverse. Frequency of pDDIs varied by study, but was most commonly between one and five pDDIs per patient. Fifty-eight percent of patients were exposed to at least one pDDI during their intensive care unit admission. Types of pDDIs identified were numerous, with aspirin being the most common drug involved. As expected, not all pDDIs were clinically significant. Clinical significance was determined by varied definitions and sources., Conclusions: Improving the understanding of clinically significant pDDIs and alerts that clinicians encounter may guide better development of surveillance through clinical decision support and decrease alert fatigue.

Acute respiratory distress syndrome (ARDS) remains a common complication associated with significant negative outcomes in critically ill patients. Lung-protective mechanical ventilation strategies remain the cornerstone in the management of ARDS. Several therapeutic options are currently available including fluid management, neuromuscular blocking agents, prone positioning, extracorporeal membrane oxygenation, corticosteroids, and inhaled pulmonary vasodilating agents (prostacyclins and nitric oxide). Unfortunately, an evidence-based, standard-of-care approach in managing ARDS beyond lung-protective ventilation remains elusive, contributing to significant variability in clinical practice. Although the optimal therapeutic strategy for managing moderate to severe ARDS remains extremely controversial, therapies supported with more robust clinical evidence should be considered first. The purpose of this narrative review is to discuss the published clinical evidence for both pharmacologic and nonpharmacologic management strategies in adult patients with moderate to severe ARDS as well as to discuss practical considerations for implementation.

Shock syndromes are associated with unacceptably high rates of mortality in critically ill patients despite advances in therapeutic options. Vasodilatory shock is the most common type encountered in the intensive care unit. It is manifested by cardiovascular failure, peripheral vasodilatation, and arterial hypotension leading to tissue hypoperfusion and organ failure. Hemodynamic support is typically initiated with fluid resuscitation strategies and administration of adrenergic vasopressor agents in nonresponsive patients to restore arterial pressure with subsequent adequate organ reperfusion. Unfortunately, high catecholamine dosing requirements may be necessary to achieve targeted hemodynamic goals that may increase the risk of vasopressor-induced adverse events. The purpose of this article is to review the clinical efficacy and safety data and potential role in therapy for catecholamine-sparing agents in vasodilatory shock. Adjunctive therapeutic options to reduce vasoactive support requirements without compromising arterial pressure include arginine vasopressin and analogs, corticosteroids, midodrine, methylene blue, and angiotensin II. Although concomitant vasopressin and corticosteroids have a more defined role in evidence-based guidelines for managing shock, clinicians may consider other potential catecholamine-sparing agents., (© 2018 Pharmacotherapy Publications, Inc.)

Purpose: The objective of this study was to evaluate AKI incidence with concomitant vancomycin and piperacillin/tazobactam (PTZ) compared to vancomycin and cefepime (FEP) in critically ill patients., Materials and Methods: A retrospective, cohort study was conducted in adult critically ill patients from January 1, 2014 to December 31, 2017. The primary aim was to compare the incidence of AKI during concomitant therapy or until hospital discharge. Secondary analyses included AKI severity, time to AKI as well as recovery, and clinical outcomes., Results: Overall, 333 patients were evaluated. The AKI rate in the vancomycin/PTZ group and vancomycin/FEP group were similar (19.5% vs. 17.3%, respectively, p = .612). Renal replacement therapy (RRT) was initiated in 10.0% and 3.8% administered vancomycin/PTZ and vancomycin/FEP groups, respectively (p = .04). Multivariate regression found vancomycin/PTZ was not associated with an increased risk of developing AKI although the presence of shock was identified as an independent risk factor (odds ratio, 3.22; 95% CI, 1.66-6.26). No significant differences in hospital or ICU length of stay or in-hospital mortality were observed between study groups., Conclusions: Concomitant PTZ and vancomycin in ICU patients was not associated with an increased risk of developing AKI compared to FEP and vancomycin combinations. More patients administered vancomycin/PTZ received RRT., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Exposure of organisms to high temperatures and various chemical and physical stressors can cause protein misfolding and aggregation. In turn, this can disrupt the functions of proteins, threatening both development and homeostasis. To overcome this, cells can initiate the highly conserved heat shock (HS) stress response pathway. In eukaryotes, this is a coordinated cellular response, in which the master HS activator, heat shock factor (HSF), is rapidly recruited to the HS protein genes, and triggers the recruitment of additional coactivator proteins that facilitate gene expression. This results in the production of HS proteins that function as nuclear and cytosolic molecular chaperones, to promote refolding of proteins and prevent aggregation and increase protein degradation pathways. Here, we describe a laboratory exercise in which students visualize and quantify Green Fluorescent Protein (GFP)-tagged HSF binding to the HS protein genes in living Drosophila salivary gland nuclei as an output of chemically induced protein misfolding. Students are assigned an array of chemicals, and using the scientific literature, predict impacts of these chemicals on protein folding. Students then test the effects of their chemicals by measuring GFP-tagged HSF binding to the HS genes in salivary glands using confocal microscopy. Designed for junior and senior level students in a cell/molecular biology course, this is a two-part lab, in which student work closely with an instructor to help familiarize them with developing hypotheses supported by scientific literature and testing these hypotheses by quantitating the levels of GFP-HSF binding, using confocal microscopy of living Drosophila cells. © 2018 International Union of Biochemistry and Molecular Biology, 46(5):445-452, 2018., (© 2018 International Union of Biochemistry and Molecular Biology.)

Background: Medication safety strategies involving trigger alerts have demonstrated potential in identifying drug-related hazardous conditions (DRHCs) and preventing adverse drug events in hospitalized patients. However, trigger alert effectiveness between intensive care unit (ICU) and general ward patients remains unknown. The objective was to investigate trigger alert performance in accurately identifying DRHCs associated with laboratory abnormalities in ICU and non-ICU settings., Methods: This retrospective, observational study was conducted at a university hospital over a 1-year period involving 20 unique trigger alerts aimed at identifying possible drug-induced laboratory abnormalities. The primary outcome was to determine the positive predictive value (PPV) in distinguishing drug-induced abnormal laboratory values using trigger alerts in critically ill and general ward patients. Aberrant lab values attributed to medications without resulting in an actual adverse event ensuing were categorized as a DRHC., Results: A total of 634 patients involving 870 trigger alerts were included. The distribution of trigger alerts generated occurred more commonly in general ward patients (59.8%) than those in the ICU (40.2%). The overall PPV in detecting a DRHC in all hospitalized patients was 0.29, while the PPV in non-ICU patients (0.31) was significantly higher than the critically ill (0.25) ( p = 0.03). However, the rate of DRHCs was significantly higher in the ICU than the general ward (7.49 versus 0.87 events per 1000 patient days, respectively, p < 0.0001). Although most DRHCs were considered mild or moderate in severity, more serious and life-threatening DRHCs occurred in the ICU compared with the general ward (39.8% versus 12.4%, respectively, p < 0.001)., Conclusions: Overall, most trigger alerts performed poorly in detecting DRHCs irrespective of patient care setting. Continuous process improvement practices should be applied to trigger alert performance to improve clinician time efficiency and minimize alert fatigue., Competing Interests: Conflict of interest statement: The authors declare that there is no conflict of interest.

Purpose: The objective of this study was to evaluate the short-term hemodynamic effects as well as vasopressor requirements with concomitant vasopressin (AVP) and hydrocortisone (HCT) compared to either agent alone in refractory septic shock., Materials and Methods: This was a retrospective, cohort study conducted in adult septic shock patients. Patients received continuous infusion AVP at 0.04units/min and/or HCT 200-300mg intravenous daily in divided doses for refractory septic shock. Refractory septic shock was defined as systolic or mean blood pressure (MAP) of <90mmHg or <70mmHg, respectively, despite fluid resuscitation and requiring norepinephrine., Results: A total of 300 patients were evaluated. The rate of achieving a "response" (norepinephrine dose reduction by ≥50% without any decrease in MAP) at 4h from baseline was significantly higher in patients receiving concomitant AVP/HCT (88.5%) compared to HCT alone (62.3%) or AVP alone (72.9%) (p=0.0005). The AVP/HCT group had higher "response" rates over the HCT and AVP monotherapy groups at 12 (p=0.052) and 24h (p=0.036). Multivariate regression showed combination therapy to be independently associated with response at 4h., Conclusions: Concomitant AVP and HCT was associated with an immediate, additive catecholamine-sparing effect over either agent alone in patients with refractory septic shock., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: To provide ICU clinicians with evidence-based guidance on safe medication use practices for the critically ill., Data Sources: PubMed, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, CINAHL, Scopus, and ISI Web of Science for relevant material to December 2015., Study Selection: Based on three key components: 1) environment and patients, 2) the medication use process, and 3) the patient safety surveillance system. The committee collectively developed Population, Intervention, Comparator, Outcome questions and quality of evidence statements pertaining to medication errors and adverse drug events addressing the key components. A total of 34 Population, Intervention, Comparator, Outcome questions, five quality of evidence statements, and one commentary on disclosure was developed., Data Extraction: Subcommittee members were assigned selected Population, Intervention, Comparator, Outcome questions or quality of evidence statements. Subcommittee members completed their Grading of Recommendations Assessment, Development, and Evaluation of the question with his/her quality of evidence assessment and proposed strength of recommendation, then the draft was reviewed by the relevant subcommittee. The subcommittee collectively reviewed the evidence profiles for each question they developed. After the draft was discussed and approved by the entire committee, then the document was circulated among all members for voting on the quality of evidence and strength of recommendation., Data Synthesis: The committee followed the principles of the Grading of Recommendations Assessment, Development, and Evaluation system to determine quality of evidence and strength of recommendations., Conclusions: This guideline evaluates the ICU environment as a risk for medication-related events and the environmental changes that are possible to improve safe medication use. Prevention strategies for medication-related events are reviewed by medication use process node (prescribing, distribution, administration, monitoring). Detailed considerations to an active surveillance system that includes reporting, identification, and evaluation are discussed. Also, highlighted is the need for future research for safe medication practices that is specific to critically ill patients.

Objective: To evaluate the quality of available evidence of drug class combinations and their association with the development of acute kidney injury (AKI)., Data Sources: A search of MEDLINE and Embase databases was completed using the following terms: "risk factor AND (acute kidney injury or acute kidney failure) AND (drug or medication).", Study Selection and Data Extraction: Inclusion criteria were the following: English language, full-text availability, and at least 1 drug-combination. Each citation was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) criteria. The literature was evaluated using the quality of evidence component of GRADE. No standardized definition of AKI was applied throughout.., Data Synthesis: Out of 2139 total citations, 151 were assessed for full-text review, with 121 citations (6%) meeting inclusion criteria, producing76 unique drug class combinations. Overall, 56 combinations (73.7%) were considered very low quality; 12 (15.8%) were considered low quality. There were 8 (10.5%) of moderate quality, and no combination was considered high quality. 58 (76%) combinations that had a single citation,with a mean of 1.6 citations per drug class combination. The combination of nonsteroidal anti-inflammatory drugs (NSAIDs) and diuretics was reported in 10 citations, the largest number of citations., Conclusions: Our study demonstrates a lack of well-designed studies addressing drug class combination-associated AKI. The combination of NSAIDs and diuretics with or without additional renin-angiotensin aldosterone agents had the strongest level of evidence. Despite limitations, the information included in this review may result in additional scrutiny about combining certain individual nephrotoxic drugs.

Objectives: Stress ulcer prophylaxis is commonly administered to critically ill patients for the prevention of clinically important stress-related mucosal bleeding from the upper gastrointestinal tract. Despite widespread incorporation of stress ulcer prophylaxis into practice around the world, questions are emerging about its indications and impact. This clinically focused article will review current controversies related to stress ulcer prophylaxis for critically ill adult patients, including bleeding frequency, risk factors, comparative efficacy, adverse effect profile, and overall cost-effectiveness of the available stress ulcer prophylaxis regimens., Data Sources: A MEDLINE search was conducted from inception through August 2015., Study Selection: Selected publications describing stress ulcer prophylaxis in adult patients were retrieved (original research, systematic reviews, and practice guidelines); their bibliographies were also reviewed to identify additional pertinent publications., Data Extraction: Data from relevant publications were abstracted and summarized., Data Synthesis: The existing evidence is organized to describe the patients most likely to benefit from stress ulcer prophylaxis, review the comparative efficacy of proton pump inhibitors and histamine 2 receptor antagonists, the adverse effects of stress ulcer prophylaxis, and overall cost-effectiveness., Conclusions: Many stress ulcer prophylaxis recommendations are based on older studies at risk of bias, which may not be applicable to modern practice. Stress ulcer prophylaxis should be limited to patients considered to be at high risk for clinically important bleeding. When evaluating only the trials at low risk for bias, the evidence does not clearly support lower bleeding rates with proton pump inhibitors over histamine 2 receptor antagonists; however, proton pump inhibitors appear to be the dominant drug class used worldwide today. The current rate of upper gastrointestinal bleeding and the relative adverse effects of acid suppression on infectious risk may drive not only the effectiveness, but also the cost-effectiveness of stress ulcer prophylaxis today. Research is currently underway to better address these issues.

Background: Phenytoin is a common medication for seizure treatment and prophylaxis in the intensive care unit (ICU). The clinical utility of the Sheiner-Tozer equation for adjusting total phenytoin levels for hypoalbuminemia remains controversial., Objective: The purpose of this study was to evaluate the correlation of this formula in predicting phenytoin serum concentrations., Methods: A retrospective cohort study was conducted in the adult ICU between January 1, 2010, and June 21, 2013. Patients meeting the following study criteria were included: age ≥18 years, admission to the ICU, simultaneously drawn total and free serum phenytoin concentrations with albumin ≤48 hours of phenytoin draws. Study end points were the correlation as well as the level of agreement in the interpretation of the free and adjusted phenytoin concentrations using the Sheiner-Tozer formula in critically ill patients with hypoalbuminemia., Results: A total of 238 patients were analyzed. Mean adjusted total phenytoin and free levels were 16.1 ± 8.1 and 1.5 ± 0.8 µg/mL, respectively (r = 0.817; P < 0.001). Absolute agreement with level interpretation between adjusted total phenytoin and free levels was 77% (κ = 0.633; P < 0.001). Adjusted phenytoin serum concentrations more frequently overestimated the free level., Conclusions: There is a significant correlation between free and adjusted total phenytoin levels using the Sheiner-Tozer equation in critically ill patients. However, disagreement was noted with interpretation, primarily because of the adjusted concentration overestimating the free level. This imprecision may lead to inaccurate decision making regarding the management of phenytoin in this patient population. Thus, free phenytoin levels should be utilized., (© The Author(s) 2016.)

Purpose: Appropriate utilization of stress ulcer prophylaxis should be limited to high-risk, intensive care unit (ICU) patients. However, inappropriate stress ulcer prophylaxis use among all hospitalized patients remains a concern. The purpose of this study was to evaluate the clinical and economic impact of a novel pharmacist-managed stress ulcer prophylaxis program in ICU and general ward patients., Methods: This retrospective, pre- and poststudy design was conducted in adult ICU and general ward patients at a large academic medical center between January 1, 2011 and January 31, 2012 to compare the rates of inappropriate stress ulcer prophylaxis before and after the implementation of a pharmacist-led stress ulcer prophylaxis management program., Results: A total of 1134 unique patients consisting of 16,415 patient days were evaluated. The relative reduction in the rate of inappropriate stress ulcer prophylaxis days after program implementation in ICU and general ward patients was 58.3% and 83.5%, respectively (P < .001). The rates of ICU patients inappropriately continued on stress ulcer prophylaxis upon hospital discharge in the pre- and postimplementation groups were 29.9% and 3.6%, respectively (P < .001), whereas general ward patients significantly decreased from 36.2% to 5.4% in the pre- and postimplementation groups, respectively (P < .001). Total inpatient costs associated with all stress ulcer prophylaxis administered was $20,052.70 in the pre- and $3280.49 in the postimplementation group (P < .001), resulting in an estimated cost savings of > $200,000 annually. No differences in clinical outcomes were observed., Conclusions: The implementation of a pharmacist-managed stress ulcer prophylaxis program was associated with a decrease in inappropriate acid suppression rates during hospitalization and upon discharge, as well as significant cost savings., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: Prior research indicates that off-label use is common in the ICU; however, the safety of off-label use has not been assessed. The study objective was to determine the prevalence of adverse drug reactions associated with off-label use and evaluate off-label use as a risk factor for the development of adverse drug reactions in an adult ICU population., Design: Multicenter, observational study, Setting: : Medical ICUs at three academic medical centers., Patients: Adult patients (age ≥ 18 yr old) receiving medication therapy., Interventions: All administered medications were evaluated for Food and Drug Administration-approved or off-label use. Patients were assessed daily for the development of an adverse drug reaction through active surveillance. Three adverse drug reaction assessment instruments were used to determine the probability of an adverse drug reaction resulting from drug therapy. Severity and harm of the adverse drug reaction were also assessed. Cox proportional hazard regression was used to identify a set of covariates that influenced the rate of adverse drug reactions., Measurements and Main Results: Overall, 1,654 patient-days (327 patients) and 16,391 medications were evaluated, with 43% of medications being used off-label. One hundred and sixteen adverse drug reactions were categorized dichotomously (Food and Drug Administration or off-label), with 56% and 44% being associated with Food and Drug Administration-approved and off-label use, respectively. The number of adverse drug reactions for medications administered and the number of harmful and severe adverse drug reactions did not differ for medications used for Food and Drug Administration-approved or off-label use (0.74% vs 0.67%; p = 0.336; 33 vs 31 events, p = 0.567; 24 vs 24 events, p = 0.276). Age, sex, number of high-risk medications, number of off-label medications, and severity of illness score were included in the Cox proportional hazard regression. It was found that the rate of adverse drug reactions increases by 8% for every one additional off-label medication (hazard ratio = 1.08; 95% CI, 1.018-1.154)., Conclusion: Although adverse drug reactions do not occur more frequently with off-label use, adverse drug reaction risk increases with each additional off-label medication used.

Introduction: Adverse events in the intensive care unit (ICU) may be associated with several possible causes, so determining a drug-related causal assessment is more challenging than in general ward patients. Therefore, the hypothesis was that automated trigger alerts may perform differently in various patient care settings. The purpose of this study was to compare the frequency and type of clinically significant automated trigger alerts in critically ill and general ward patients as well as evaluate the performance of alerts for drug-related hazardous conditions (DRHCs)., Methods: A retrospective cohort study was conducted in adult ICU and general ward patients at three institutions (academic, community, and rural hospital) in a health system. Automated trigger alerts generated during two nonconsecutive months were obtained from a centralized database. Pharmacist responses to alerts and prescriber response to recommendations were evaluated for all alerts. A clinical significant event was defined as an actionable intervention requiring drug therapy changes that the pharmacist determined to be appropriate for patient safety and where the physician accepted the pharmacist's recommendation. The positive predictive value (PPV) was calculated for each trigger alert considered a DRHC (i.e., abnormal laboratory values and suspected drug causes)., Results: A total of 751 alerts were generated in 623 patients during the study period. Pharmacists intervened on 39.8 and 44.8 % alerts generated in the ICU and general ward, respectively. Overall, the physician acceptance rate of approximately 90 % was comparable irrespective of patient care setting. Therefore, the number of clinically significant alerts was 88.9 and 83.4 % for the ICU and non-ICU, respectively. The types of drug therapy changes were similar between settings. The PPV of alerts identifying a DRHC was 0.66 in the ICU and 0.76 in general ward patients., Conclusions: The number and type of clinically significant alerts were similar irrespective of patient population, suggesting that the alerts may be equally as beneficial in the ICU population, despite the challenges in drug-related event adjudication. An opportunity exists to improve the performance of alerts in both settings, so quality improvement programs for measuring alert performance and making refinements is needed.

Opioids are the cornerstone of pain management; however, their use is associated with a variety of adverse drug events (ADEs) ranging from nausea and vomiting to urinary retention and respiratory depression. The purpose of this review is to describe the frequency and cost associated with different types of opioid-related ADEs to better understand their economic impact. A search of studies published in journals from 1946 to December, 2013, was conducted using MEDLINE and EMBASE. A total of 20 articles were reviewed. Data reflect a substantial economic burden of opioid-related ADEs resulting in high hospital costs, prolonged hospital stays, and substantial health care resource usage. Nausea, vomiting, and constipation are frequent and increased costs occur in all types of pain (surgical, nonsurgical, cancer, noncancer) in both inpatients and outpatients. Given the large economic burden of opioid-related ADEs, prevention rather than treatment may be the most effective strategy.

Pulmonary arterial hypertension (PAH) remains a progressive disease without a cure, despite the development of several treatment options over the past several decades. Its management strategy consists of the endothelin receptor antagonists (ambrisentan, bosentan, macitentan), phosphodiesterase-5 inhibitors (sildenafil, tadalafil, vardenafil), and prostacyclin analogs (epoprostenol, treprostinil, iloprost). Treprostinil, a stable prostacyclin analog, displays vasodilatory effects in the pulmonary vasculature, as well as antiplatelet aggregation properties. Clinical practice guidelines recommend oral endothelin receptor antagonist or phosphodiesterase inhibitor therapy in mild to moderate PAH. Epoprostenol is specifically suggested as first-line therapy in moderate to severe PAH patients (ie, World Health Organization/New York Heart Association functional class III-IV). However, treprostinil may be an alternative option in these severe PAH patients. The longer half-life and stability at room temperature with treprostinil may be associated with lower risk of pulmonary hemodynamic worsening as a result of abrupt infusion discontinuation and less frequent drug preparation. These characteristics make treprostinil an attractive alternative to continuous infusion of epoprostenol, due to convenience and patient safety. The purpose of this review is to evaluate the safety and efficacy of continuous infusion of treprostinil as well as the inhaled and oral routes of administration in PAH.

Introduction: Therapeutic opioid use continues to grow, with greater than a fivefold increase in usage of fentanyl-based products over a 10-year period. Opioids are known for their side-effect profile, including bradycardia and respiratory depression; questions remain, however, regarding lesser known side effects such as opioid-induced hyperalgesia (OIH)., Areas Covered: A systematic review of published literature addressing remifentanil OIH in the surgical setting was completed. A search was conducted of PubMed, Embase and Ovid from 1946 until June 2013. Inclusion criteria consisted of age ≥ 18 years, humans, full-text articles and English language. A total of 35 unique articles were included. Sixteen articles reported outcomes that supported remifentanil OIH and 6 that refuted and 22 were focused on prevention., Expert Opinion: There is conflicting evidence regarding the existence of remifentanil OIH. Outcomes evaluating measures of hyperalgesia frequently conclude that remifentanil OIH exists, while those evaluating opioid consumption do not. Therefore, remifentanil does induce a degree of hyperalgesia, but we do not believe that it reaches a level of clinical significance that requires prevention. If a significant concern for the development of remifentanil OIH is suspected, we suggest using the least possible effective dose of remifentanil as the primary prevention strategy.

Over the past twenty years, exciting developments in optical and molecular imaging approaches have allowed researchers to examine with unprecedented resolution the spatial organization of transcription sites in the nucleus. An attractive model that has developed from these studies is that active genes cluster to preformed transcription factories that contain multiple active RNA polymerases and transcription factor proteins required for efficient mRNA biogenesis. However, this model has been extensively debated in part due to the fact transcription factories and their features have only been documented in fixed cells. In this review, we will focus on recent live-cell imaging studies that are changing our understanding of transcription factories., (Copyright © 2014. Published by Elsevier Ltd.)

Acute respiratory distress syndrome (ARDS) and acute lung injury (ALI) are conditions associated with an estimated mortality of 40–50%. The use of inhaled vasodilators can help to improve oxygenation without hemodynamic effects. This article reviews relevant studies addressing the safety and efficacy of inhaled nitric oxide (iNO) and aerosolized epoprostenol (aEPO) in the treatment of life-threatening hypoxemia associated with ARDS and ALI. In addition, the article also provides a practicable guide to the clinical application of these therapies. Nine prospective randomized controlled trials were included for iNO reporting on changes in oxygenation or clinical outcomes. Seven reports of aEPO were examined for changes in oxygenation. Based on currently available data, the use of either iNO or aEPO is safe to use in patients with ALI or ARDS to transiently improve oxygenation. No differences have been observed in survival, ventilator-free days, or attenuation in disease severity. Further studies with consistent end points using standard delivery devices and standard modes of mechanical ventilation are needed to determine the overall benefit with iNO or aEPO.

Fifty-five thousand patients are cared for in the intensive care unit (ICU) daily with sedation utilized to reduce anxiety and agitation while optimizing comfort. The Society of Critical Care Medicine (SCCM) released updated guidelines for management of pain, agitation, and delirium in the ICU and recommended nonbenzodiazepines, such as dexmedetomidine and propofol, as first line sedation agents. Dexmedetomidine, an alpha-2 agonist, offers many benefits yet its use is mired by the inability to consistently achieve sedation goals. Three hypotheses including patient traits/characteristics, pharmacokinetics in critically ill patients, and clinically relevant genetic polymorphisms that could affect dexmedetomidine response are presented. Studies in patient traits have yielded conflicting results regarding the role of race yet suggest that dexmedetomidine may produce more consistent results in less critically ill patients and with home antidepressant use. Pharmacokinetics of critically ill patients are reported as similar to healthy individuals yet wide, unexplained interpatient variability in dexmedetomidine serum levels exist. Genetic polymorphisms in both metabolism and receptor response have been evaluated in few studies, and the results remain inconclusive. To fully understand the role of dexmedetomidine, it is vital to further evaluate what prompts such marked interpatient variability in critically ill patients.

The kinetics with which promoter-proximal paused RNA polymerase II (Pol II) undergoes premature termination versus productive elongation is central to understanding underlying mechanisms of metazoan transcription regulation. To assess the fate of Pol II quantitatively, we tracked photoactivatable GFP-tagged Pol II at uninduced Hsp70 on polytene chromosomes and showed that Pol II is stably paused with a half-life of 5 min. Biochemical analysis of short nascent RNA from Hsp70 reveals that this half-life is determined by two comparable rates of productive elongation and premature termination of paused Pol II. Importantly, heat shock dramatically increases elongating Pol II without decreasing termination, indicating that regulation acts at the step of paused Pol II entry to productive elongation.