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Edward T Van Matre,1 Deb S Sherman,2 Tyree H Kiser1,21Department of Clinical Pharmacy, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, 2Department of Pharmacy, University of Colorado Hospital, Aurora, CO, USAAbstract: Intracerebral hemorrhage (ICH) is a neurologic injury resulting in significant morbidity and mortality. Statins play a significant role in primary and secondary prevention of cardiovascular and cerebrovascular ischemic events. Despite clear benefits of statins in ischemic stroke, post hoc analyses of some studies suggest there may be a link between statin therapy and development of ICH. Direct pharmacologic effects of decreased serum levels of total cholesterol and low-density lipoproteins in conjunction with pleiotropic effects are thought to be linked to this possible increase in ICH risk. In the face of the potential of statins to increase the risk of ICH, recent evidence suggests that statins may also have beneficial effects on patient outcomes when continued or initiated following an ICH. This discordance in findings and the overall lack of well-designed prospective clinical trials increase the complexity of clinical decision making when utilizing statin therapy in patients with, or at risk for, ICH. This review evaluates the pharmacologic effects of statin therapy and describes how these effects translate to both risks and benefits in ICH. The current literature regarding the effects of statin therapy on clinical outcomes in ICH is evaluated to help guide clinicians with decisions regarding initiation, continuation, or discontinuation of statin therapy in patients with ICH.Keywords: intracerebral hemorrhage, statin pharmacology, intracranial hemorrhage, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, pleiotropic effects

Background. Vasopressin is frequently utilized for a variety of shock states in critically ill patients. Short stability (≤24 hours) after intravenous admixture with current manufacturer labeling requires just in time preparation and may lead to delays in therapy and increased medication waste. We aimed to evaluate vasopressin stability in 0.9% sodium chloride stored in polyvinyl chloride bags and polypropylene syringes for up to 90 days. Additionally, we evaluated the impact of extended stability on the time to administration and cost savings from reduced medical waste at an academic medical center. Methods. Dilutions of vasopressin to concentrations of 0.4 and 1.0 unit/mL were performed under aseptic conditions. The bags and syringes were stored at room temperature (23°C-25°C) or under refrigeration (3°C-5°C). Three samples of each preparation and storage environment were analyzed on days 0, 2, 14, 30, 45, 60, and 90. Physical stability was performed by visual examination. The pH was assessed at each point and upon final degradation evaluation. Sterility of the samples was not assessed. Chemical stability of vasopressin was evaluated using liquid chromatography with tandem mass spectrometry. Samples were considered stable if there was <10% degradation of the initial concentration. Results. Vasopressin diluted to 0.4 and 1.0 unit/mL with 0.9% sodium chloride injection was physically stable throughout the study. No precipitation was observed. At days 2, 14, 30, 45, 60, and 90 all bags and syringes diluted to 0.4 units/mL had <10% degradation. Vasopressin diluted to 1 unit/mL and stored under refrigeration had <10% degradation at all measured days, but when stored under room temperature was found to have >10% degradation at day 30. Implementation of a batching process resulted in reduced waste ($185 300) and improved time to administration (26 vs 4 minutes). Conclusion. Vasopressin diluted to a concentration of 0.4 units/mL with 0.9% sodium chloride injection is stable for 90 days at room temperature and under refrigeration. When diluted to 1.0 unit/mL with 0.9% sodium chloride injection it is stable for 90 days under refrigeration. Use of extended stability and sterility testing to batch prepare infusions may lead to improved time to administration and cost savings from reduced medication waste., Competing 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) 2022.)

Purpose: Evaluate the stability of isoproterenol hydrochloride injection in 0.9% sodium chloride in polyvinyl chloride bags for up to 90 days. Methods: Dilutions of isoproterenol hydrochloride injection to a concentration of 4 μg/mL were performed under aseptic conditions. The bags were stored in amber ultraviolet light blocking bags at room temperature (23°C-25°C) or under refrigeration (3°C-5°C). Three samples of each preparation and storage environment were analyzed on days 0, 2, 14, 30, 45, 60, and 90. Physical stability was performed by visual examination. The pH was assessed at baseline, each analysis day, and upon final degradation evaluation. Sterility of the samples was not assessed. Chemical stability of isoproterenol hydrochloride was evaluated using liquid chromatography with tandem mass spectrometry. Samples were considered stable if there was <10% degradation of the initial concentration. Results: Isoproterenol hydrochloride diluted to 4 μg/mL with 0.9% sodium chloride injection was physically stable throughout the study. No precipitation was observed. At days 2, 14, 30, 45, 60, and 90 all bags diluted to 4 μg/mL had <10% degradation when stored under refrigeration (3°C-5°C) or stored at room temperature (23°C-25°C). Conclusion: Isoproterenol hydrochloride diluted to a concentration of 4 μg/mL with 0.9% sodium chloride for injection in ultraviolet light blocking bags was stable for 90 days at room temperature and under refrigeration., Competing 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) 2022.)

The intent of this study was an evaluation of our effort to reduce the incidence of hypercalcemia in critically ill vitamin D-deficient patients with multiple traumatic injuries given cholecalciferol. Vitamin D deficiency was defined as a serum 25-hydroxy vitamin D concentration (25-OH vit D) of <20 ng/mL. Adult patients (>17 years of age) were given 10,000 IU of cholecalciferol daily with an intended target 25-OH vit D of >19.9 ng/mL. These patients were compared to a historical control group that underwent therapy with a higher target of >29.9 ng/mL. Patients received cholecalciferol via the feeding tube along with enteral nutrition (EN) until the target 25-OH vit D was achieved, EN discontinued, the nutrition support service signed off the patient, or the patient was discharged from the TICU. Patients were included if two consecutive weekly 25-OH vit D were measured. One hundred and three critically ill trauma patients were retrospectively studied. Fifty were given cholecalciferol therapy with the new lower target 25-OH vit D, and 53 were from a historical cohort aiming for the higher target. Hypercalcemia (serum ionized calcium concentration > 1.32 mmol/L) was reduced from 40% (21 out of 53 patients) to 4% (2 out of 50 patients; p < 0.001). None of the hypercalcemic patients were symptomatic. Readjustment of target 25-OH vit D concentration resulted in a ten-fold decrease in the rate of hypercalcemia and improved the safety of cholecalciferol therapy for critically ill patients with traumatic injuries.

Dalbavancin is a synthetic lipoglycopeptide that exerts its antimicrobial activity through two distinct modes of action, inhibition of cell wall synthesis and an anchoring mechanism. Compared with previous glycopeptide antibiotics, dalbavancin demonstrates improved antibacterial potency against Gram-positive organisms and a long half-life of approximately 1 week, which is longer in tissues (e.g., skin, bone) than plasma. These factors facilitated the development of single-dose or once-weekly dosing regimens to treat acute bacterial skin and skin structure infections (ABSSSI). Dalbavancin exhibits dose-proportional pharmacokinetics and is highly protein bound (93%). Despite being highly protein bound, it has a steady-state volume of distribution >10 L and distributes widely into the skin, bone, peritoneal space, and epithelial lining fluid, but not cerebrospinal fluid. Dalbavancin elimination occurs via a combination of renal (approximately 45%) and non-renal clearance, with dose adjustments recommended only in patients with a creatinine clearance <30 mL/min not receiving any form of dialysis. The established pharmacokinetic/pharmacodynamic index associated with bacterial kill is free area under the concentration-time curve over the minimum inhibitory concentration (fAUC/MIC), with a goal 24-h fAUC/MIC of at least 27.1 for Staphylococcus aureus infections. Recent data suggest usefulness in the treatment of infections beyond ABSSSI, with convenient dosing and redosing strategies for complicated infections requiring extended treatment durations. Additional studies are needed to confirm these preliminary findings., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

The intent of this study was to ascertain the prevalence of augmented renal clearance (ARC) in patients with traumatic injuries who require nutrition therapy and identify factors associated with ARC. Adult patients admitted to the trauma intensive care unit from January 2015 to September 2016 who received enteral or parenteral nutrition therapy and had a 24 h urine collection within 4 to 14 days after injury were retrospectively evaluated. Patients with a serum creatinine concentration > 1.5 mg/dL, required dialysis, or had an incomplete urine collection were excluded. ARC was defined as a measured creatinine clearance > 149 mL/min/1.73 m 2 . Two hundred and three patients were evaluated. One hundred and two (50%) exhibited ARC. A greater proportion of patients with ARC were male (86% vs. 67%; p = 0.004), had traumatic brain injury (33% vs. 9%; p = 0.001), a higher injury severity score (30 ± 11 vs. 26 ± 12; p = 0.015), were younger (36 ± 15 vs. 54 ± 17 years; p = 0.001), had a lower serum creatinine concentration (0.7 ± 2 vs. 0.9 ± 0.2 mg/dL; p = 0.001) and were more catabolic (nitrogen balance of -10.8 ± 13.0 vs. -6.2 ± 9.2 g/d; p = 0.004). The multivariate analysis revealed African American race and protein intake were also associated with ARC. Half of critically ill patients with traumatic injuries experience ARC. Patients with multiple risk factors for ARC should be closely evaluated for dosing of renally-eliminated electrolytes, nutrients, and medications.

Background: Patients with traumatic brain (TBI) injury often require a high dosage of propofol, which can provide an excessive caloric intake. We evaluated our strategy of using liquid protein supplement boluses concurrently with high protein-containing enteral nutrition (EN) formulas and formula rate reduction to avoid caloric overfeeding and inadequate protein intake., Methods: Adult patients (aged >17 years) with TBI admitted to the trauma intensive care unit (TICU) who received concurrent propofol and EN were retrospectively reviewed. Caloric intakes from propofol and EN were obtained. Actual protein intake was compared with projected protein intakes from high protein content and standard protein content enteral formulas when given at an isocaloric intake., Results: Fifty-one patients were enrolled. Average caloric intake from propofol was 356 ± 243 kcal/d or 5 ± 3 kcal/kg/d (range, <1-15 kcal/kg/d). Daily EN caloric intake ranged from 7 ± 4 kcal/kg/d (day 2) to 16 ± 9 kcal/kg/d (day 5; P < .001). Average protein intake ranged from 0.6 ± 0.4 g/kg/d (day 2) to 1.5 ± 0.7 g/kg/d (day 5; P < .001). The modified EN strategy resulted in daily delivery of 24%-38% more protein than an isocaloric regimen with a high protein-content formula and twice as much protein than the standard protein-content formula (P < .001)., Conclusion: The strategy of providing an EN regimen comprised liquid protein boluses, and high and very high protein-containing EN formulas at a reduced rate improved protein delivery without caloric overfeeding., (© 2020 American Society for Parenteral and Enteral Nutrition.)

Dalbavancin offers a possible treatment option for infectious peritonitis associated with peritoneal dialysis (PD) due to its coverage of Gram-positive bacteria and pharmacokinetic properties. We aimed to evaluate the clinical pharmacokinetics (PK) and pharmacodynamics of dalbavancin in a prospective, randomized, open-label, crossover PK study of adult patients with end-stage renal disease ESRD who were receiving PD. Sampling occurred prior to a single 30-min infusion of dalbavancin at 1,500 mg and at 1, 2, 3, 4, and 6 h and 7 and 14 days postadministration. Concentration-time data were analyzed via noncompartmental analysis. Pharmacodynamic parameters against common infectious peritonitis-causing pathogens were evaluated. Ten patients were enrolled. Patients were a median of 55 years old and had a median weight of 78.2 kg, 50% were female, and 70% were Caucasian. The terminal plasma half-life of dalbavancin was 181.4 ± 35.5 h. The day 0 to day 14 dalbavancin mean area under the curve (AUC) was 40,573.2 ± 9,800.3 mg·h/liter. The terminal-phase half-life of dalbavancin within the peritoneal fluid was 4.309 × 10 8 ± 1.140 × 10 9  h. The day 0 to day 14 dalbavancin mean peritoneal fluid AUC was 2,125.0 ± 1,794.3 mg·h/liter. The target plasma AUC/MIC was attained with the intravenous dose in all 10 patients for all Staphylococcus and Streptococcus species at the recommended MIC breakpoints. The intraperitoneal arm of the study was stopped early, because the first 3 patients experienced moderate to severe pain and bloating within 1 h following the administration of dalbavancin. Dalbavancin at 1,500 mg administered intravenously can be utilized without dose adjustment in peritoneal dialysis patients and will likely achieve the necessary peritoneal fluid concentrations to treat peritonitis caused by typical Gram-positive pathogens., (Copyright © 2020 American Society for Microbiology.)

The package insert of 4-factor prothrombin complex concentrate (4F-PCC) contains specific dosing recommendations stating to determine the patients dose based on their INR and weight, capping the weight at 100 kg. However, the mean body mass index (BMI) in the 4F-PCC U.S. approval study was 27 kg/m 2 , and there is a lack of literature identifying the ideal dosing strategy in obesity. We conducted a retrospective analysis of obese patients (BMI ≥ 30 kg/m 2 ) who received 4F-PCC for warfarin associated emergent bleeding reversal. Treatment groups were those that received 4F-PCC on adjusted body weight (AdjBW) and those on actual body weight (ActBW). The primary outcome was the percent of patients achieving coagulopathy reversal, defined as a post-treatment INR < 1.4 for neurologic indications and < 1.5 for all others. A total of 78 obese patients were included (28 AdjBW and 50 ActBW). Baseline INR (3.1 vs. 2.8; p = 0.052) and BMI (33.6 vs. 33.6 kg/m 2 ) were similar between groups. Achievement of goal INR was significantly lower in the AdjBW group (36% vs. 68%; p = 0.006). A majority of patients had intracranial hemorrhage (32% vs. 54%; p = 0.06), and the median dose of 4F-PCC was lower in the AdjBW group (2120 vs. 2500 units; p = 0.02). Dosing 4F-PCC using adjusted body weight in obese patients resulted in a significantly lower rate of coagulopathy reversal. ActBW should be used to dose 4F-PCC in obese patients when the 100 kg dose cap is utilized per the package insert recommendations.

Acute blood pressure control after a cerebrovascular event is integral in the immediate care of these patients to preserve perfusion to ischemic areas and prevent intracerebral bleeding. The majority of patients with ischemic stroke or intracerebral hemorrhage (ICH) present with preexisting hypertension and therefore require a treatment plan after the acute phase. The presence of chronic hypertension after ICH has often been discussed as a modifiable risk factor for recurrent events. Clinical evidence is relatively lacking for clinicians to understand the extent of blood pressure lowering and the optimal agents to use in this setting. Limited data exist describing the long-term management of hypertension in patients after cerebrovascular events. This review provides nurses with a summary of the available literature on long-term blood pressure management to minimize the risk of secondary ICH and ischemic stroke. It focuses on oral antihypertensive medications available in the United States that may be utilized to manage chronic hypertension immediately after the postacute phase of care to lower blood pressure and to improve long-term outcomes.

Background: Invasive fungal infections are a major cause of morbidity and mortality. Newer antifungals may provide similar efficacy with improved safety compared to older more established treatments. This study aimed to compare clinically relevant safety and efficacy outcomes in real world patients treated with isavuconazole, voriconazole, or posaconazole., Methods: This single center retrospective matched cohort study evaluated adults between January 2015 and December 2017. The primary outcome was a composite safety analysis of antifungal related QTc prolongation, elevated liver function tests (> 5 times ULN), or any documented adverse drug event. Key secondary outcomes included: individual safety events, 30-day readmissions, magnitude of drug interactions with immunosuppressive therapy, and overall cost., Results: A total of 100 patients were included: 34 patients in the voriconazole group and 33 patients within each of the isavuconazole and posaconazole groups. The composite safety outcome occurred in 40% of the total cohort and was different between isavuconazole (24.2%), voriconazole (55.9%), and posaconazole (39.4%; p = 0.028). Change in QTc (p < 0.01) and magnitude of immunosuppression dose reduction (p = 0.029) were different between the three groups. No differences in mortality, length of stay, readmission, or infection recurrence were observed between groups (p > 0.05 for all). The overall medication cost, when including therapeutic drug monitoring, was not different between treatments (p = 0.36)., Conclusions: Patients treated with isavuconazole resulted in fewer composite safety outcomes, driven by decreased incidence of QTc prolongation, compared to patients treated with voriconazole or posaconazole. Overall drug cost was not significantly different between the treatment therapy options.

Background: Venous thromboembolism (VTE) occurs frequently in critically ill patients without heparin prophylaxis. Although heparin prevents VTE, VTEs occur frequently despite prophylaxis. A higher heparin dosage may be more effective for preventing VTE., Methods: A retrospective study was conducted using the Premier Incorporated Perspective Database to evaluate comparatively the effects of different heparin prophylaxis dosing strategies in the critically ill patient. Critically ill adult patients who were mechanically ventilated for at least 1 day and had an intensive care unit (ICU) length of stay of at least 2 days were included. Patients received 5000 units of heparin either twice/day or 3 times/day. The primary outcome was development of a new VTE. Key secondary outcomes included clinically important bleeding, thrombocytopenia, and mortality. Patients were propensity matched to control for confounding. Multivariable analysis was conducted for VTE risk factors., Results: The study included 30,800 patients from 374 hospitals who were propensity matched by heparin dosage. New VTE occurred in 6.16% of patients treated with 3 times/day heparin versus 6.23% with twice/day heparin (p=0.8). No significant differences in the incidence of pulmonary embolism (0.91% vs 0.8%, p=0.29) or deep vein thrombosis (5.56% vs 5.70% p=0.59) were observed between the two types of heparin dosing. No differences were observed between the two types of heparin dosing in in-hospital mortality (15.8% vs 15.15%), bleeding (0.23% vs 0.33%), or thrombocytopenia (5.19% vs 5.34%, p>0.08 for all), respectively. Risk factors associated with VTE included intraabdominal and urinary tract infections, loop diuretics, malnutrition, obesity, thrombocytopenia, paralytics, vasopressors, female sex, peripheral vascular disease, sepsis, neutropenia, and end-stage renal disease. Antiplatelet therapy, heart failure, diabetes, and substance abuse were associated with reduced VTE (p<0.05 for all)., Conclusions: In critically ill patients, prophylactic dosing of heparin 3 times/day versus twice/day was not associated with differences in new VTE or safety outcomes. Several modifiable VTE risk factors were identified., (© 2019 Pharmacotherapy Publications, Inc.)

The central nervous system (CNS) and gastrointestinal tract (GIT) are linked through neuro-endocrine and humoral pathways. Critically ill patients suffer severe physical and emotional stress and frequently receive acid suppressants; however, stress and acid suppression may alter GIT microbiota. This study evaluated the effects of acid suppression on the GIT microbiota and genome-wide expression of brain-specific genes in a murine model of restraint stress. Twenty-four male C57BL/6J mice were randomly assigned to three days of restraint stress by hypothermic immobilization or control environment for three hours daily and either esomeprazole 2 mg/kg or saline by intraperitoneal injection daily. Bacterial communities associated with the stomach, ileum, cecum, and mid-colon were determined by broad-range 16S rRNA gene sequencing, while RNA-sequencing assessed mRNA expression in the hippocampus. Both stress (p < 0.001) and esomeprazole (p = 0.006) had significant, independent effects on the composition of stomach microbiota. Stress had no impact on the hippocampus but the addition of esomeprazole induced differential expression of 124 genes, many of which are involved in cognitive and behavior pathways. Gene expression was correlated with the abundances of multiple microbial families. Acute stress has region-specific effects on the distribution of GIT commensal bacteria which is heightened with acid suppression. Several key biological processes in the hippocampus that are needed for neurocognition are affected by dysbiosis caused by acid suppression during stress. Further studies should evaluate associations between microbiota, host gene expression, the abundance of CNS neurocognitive modulators, and their impact on cognition and behavior., (Copyright © 2018 IBRO. Published by Elsevier Ltd. All rights reserved.)

Essentials Critically ill cancer patients require pharmacologic prophylaxis for venous thromboembolism (VTE). Patients from 566 hospitals in the United States between 2010 and 2014 were included. Low-molecular-weight heparin (LMWH) prophylaxis was not associated in a reduction of VTE rates. LMWH prophylaxis was associated with a reduction in bleeding and heparin induced thrombocytopenia. SUMMARY: Background Critically ill patients with cancer are at increased risk of venous thromboembolism (VTE) from physical and cellular factors, requiring pharmacologic prophylaxis to reduce the risk of VTE. Objectives To assess whether low-molecular-weight heparin (LMWH) prophylaxis reduces in-hospital rates of VTE or improves clinical outcomes compared with unfractionated heparin (UFH) prophylaxis in critically ill patients with cancer. Methods We used a propensity-matched comparative-effectiveness cohort from the Premier Database. Patients aged 18 years or older with a primary diagnosis of cancer, intensive care unit admission and VTE prophylaxis within 2 days of admission between 1 January 2010 and 31 December 2014 were included. Patients were divided into LMWH or UFH prophylaxis groups. Results A total of 103 798 patients were included; 75 321 (72.6%) patients received LMWH and 28 477 (27.4%) patients received UFH. Propensity analysis matched (2 : 1) 42 343 LMWH patients and 21 218 UFH patients. Overall, LMWH was not associated with a decreased incidence of VTE (5.32% vs. 5.50%). LMWH prophylaxis was associated with a reduction in pulmonary embolism (0.70% vs. 0.99%), significant bleeding (13.3% vs. 14.8%) and heparin-induced thrombocytopenia (HIT) (0.06% vs. 0.19%). In non-metastatic solid disease, LMWH was associated with decreased VTE (4.27% vs. 4.84%) and PE (0.47% vs. 0.95%). Conclusions The use of an LMWH for VTE prophylaxis was not associated with a reduction in the incidence of in-hospital VTE as compared with UFH, but was associated with significant reductions in PE, clinically important bleeding events, and incidence of HIT in critically ill patients with cancer., (© 2018 International Society on Thrombosis and Haemostasis.)

Purpose: Neurocritically ill patients have clinically significant alterations in pharmacokinetic parameters of renally eliminated medications that may result in subtherapeutic plasma and cerebrospinal fluid antibiotic concentrations., Methods: We conducted a prospective randomized open-label study of adult neurocritically ill patients treated with vancomycin and cefepime. Vancomycin 15 mg/kg and cefepime 2 g were dosed at every-8- or 12-hour intervals. The primary outcomes were the achievement of pharmacodynamic (PD) targets related to time of unbound drug above minimum inhibitory concentrations (MIC) for 60% or more of the dosing interval (fT > MIC ≥ 60%) for β-lactams and ratio of 24-hour area under the curve (AUC):MIC of 400 or greater for vancomycin., Results: Twenty patients were included in the study. They were divided equally between the every-12-hour and every-8-hour dosing groups. Patients (mean age 51.8 ± 11 yrs) were primarily male (60%) and white (95%), and most had an admission diagnosis of intracranial hemorrhage (80%). Compared with the every-12-hour group, the every-8-hour vancomycin group achieved target trough concentrations (higher than 15 μg/ml) significantly more frequently at initial measurement (0% vs 80%, p<0.01) and at 7-10 days (0% vs 90%, p=0.045) and achieved PD targets more frequently at increasing MICs. Similarly, compared with every-12-hour dosing, the every-8-hour cefepime dosing strategy significantly increased PD target attainment (fT > MIC ≥ 60%) at an MIC of 8 μg/ml (20% vs 70%, p=0.02)., Conclusions: This study demonstrated that more frequent dosing of vancomycin and cefepime is required to achieve optimal PD targets in adult neurocritically ill patients. The need for increased total daily doses is potentially secondary to the development of augmented renal clearance., (© 2018 Pharmacotherapy Publications, Inc.)

Infections account for 15-20% of deaths in transplant recipients, requiring rapid and appropriate therapeutic interventions. Many anti-infective agents interact with immunosuppressive regimens used in transplantation, placing patients at increased risk for adverse drug reactions and prolonged hospitalizations. There is established data regarding the level of evidence and magnitude of interactions between calcineurin inhibitors and mammalian target of rapamycin inhibitors with anti-infective agents. Less is known about the interactions with anti-proliferative agents and corticosteroids, with gaps in knowledge on the appropriate management of these interactions. The objective of this review was to highlight the pharmacokinetic drug-drug interactions between antimetabolites and corticosteroids with commonly used anti-infective agents.

Objective: The objective of this study was to evaluate the stability of epinephrine hydrochloride in 0.9% sodium chloride in polyvinyl chloride bags for up to 60 days. Methods: Dilutions of epinephrine hydrochloride to concentrations of 16 and 64 µg/mL were performed under aseptic conditions. The bags were then placed into ultraviolet light-blocking bags and stored at room temperature (23°C-25°C) or under refrigeration (3°C-5°C). Three samples of each preparation and storage environment were analyzed on days 0, 30, 45, and 60. Physical stability was performed by visual examination. The pH was assessed at baseline and upon final degradation evaluation. Sterility of the samples was not assessed. Chemical stability of epinephrine hydrochloride was evaluated using high-performance liquid chromatography. To determine the stability-indicating nature of the assay, degradation 12 months following preparation was evaluated. Samples were considered stable if there was less than 10% degradation of the initial concentration. Results: Epinephrine hydrochloride diluted to 16 and 64 µg/mL with 0.9% sodium chloride injection and stored in amber ultraviolet light-blocking bags was physically stable throughout the study. No precipitation was observed. At days 30 and 45, all bags had less than 10% degradation. At day 60, all refrigerated bags had less than 10% degradation. Overall, the mean concentration of all measurements demonstrated less than 10% degradation at 60 days at room temperature and under refrigeration. Conclusion: Epinephrine hydrochloride diluted to 16 and 64 µg/mL with 0.9% sodium chloride injection in polyvinyl chloride bags stored in amber ultraviolet light-blocking bags was stable up to 45 days at room temperature and up to 60 days under refrigeration., 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.

BACKGROUND Levetiracetam is an antiepileptic drug frequently used in critically ill patients. Levetiracetam is primarily eliminated as a parent compound via glomerular filtration and requires dose adjustment in renal insufficiency, but the literature on patients receiving continuous veno-venous hemofiltration (CVVH) is scant. CASE REPORT We report the levetiracetam pharmacokinetic profile of a patient being treated with levetiracetam 1000 mg intravenously every 12 h who required continuous veno-venous hemofiltration (CVVH). The patient underwent CVVH utilizing a high-flux polyethersulfone membrane filter. The blood flow rate was 250 ml/min, and the predilution replacement therapy fluid flow rate was 2000 ml/h. After achieving presumed steady-state on levetiracetam 1000 mg q12h, serial plasma samples (pre- and post-filter) and effluent samples were drawn at 2, 4, 6, 8, and 10 h. Levetiracetam concentrations were determined utilizing LC-MS/MS. The levetiracetam maximum concentration (Cmax), minimum concentration (Cmin), half-life, area under the concentration-time curve (AUC0-12), clearance (CL), and volume of distribution (Vd) were 30.7 µg/ml, 16.1 µg/ml, 12.9 h, 272 mg·hr/L, 3.68 L/h, and 0.73 L/kg, respectively. The sieving coefficient was 1.03±0.08. CVVH represented 61.3% of the total levetiracetam clearance. The patient was maintained on CVVH for 24 consecutive days and then transitioned to intermittent hemodialysis and remained seizure-free. CONCLUSIONS CVVH is highly effective in removing levetiracetam from circulating plasma. Due to the effective removal, standard doses of levetiracetam are required to maintain adequate plasma concentrations. Dose reductions utilizing HD or estimated creatinine clearance recommendations will likely lead to subtherapeutic levels, especially if higher CVVH flow rates are used.

Introduction: Ensuring a culture that prioritizes and implements patient safety requires educating all future health care professionals to prepare them for their active role in reducing medical errors. There is limited literature describing integration of patient safety education into the curriculum of health care professionals, including pharmacists. The purpose of this study was to evaluate the perceived benefit of integrating patient safety education into a pharmacy curriculum., Methods: Second-year pharmacy students (P2s) completed a patient safety self-study, followed by in-class and experiential application of a root cause analysis (RCA). An electronic, anonymous postsurvey was administered to P2s and third-year pharmacy students (P3s) who had not had formal patient safety education., Results: Of the 310 students, 53% responded to the survey. Significantly more P2s reported more confidence to describe patient safety and its purpose ( P = .0092), describe factors that influence patient safety ( P = .0055), and conduct an RCA ( P < .001). P2s also reported significantly better ability to conduct a RCA compared to P3s (88.9% positive vs 58.7%, respectively; P ≤ .001)., Conclusions: Both classes perceived patient safety education to be valuable; however, formal education resulted in some significant improvements in perceived confidence and understanding, including ability to conduct an RCA.

Objectives: Valproic acid (VPA) is a broad-spectrum antiepileptic drug used for a variety of neurologic disorders. The relatively short half-life seen with intermittent intravenous bolus doing may lead to serum concentration variability. Continuous infusion VPA therapy is an approach to mitigate these effects. The objective of this study is to characterize the pharmacokinetics of continuous infusion of VPA in acutely ill patients and to determine dosing regimens that most frequently obtain goal steady-state serum concentrations., Methods: This is a retrospective pharmacokinetics study in adult patients receiving continuous infusion VPA per institutional protocol for seizure or status migrainosus. Pharmacokinetic parameters were reviewed for 234 patients (25 critically ill) and compared between the two groups (non-critically ill vs. critically ill). Intermittent and continuous infusion dosing strategies were modeled utilizing Monte Carlo simulations for both cohorts. Frequencies of serum concentration attainment were reported., Results: The percent target attainment for the non-critically ill group and critically ill group were 69.4 and 58.3% (p = 0.282) post-loading dose and 69.7 and 37.5% (p = 0.004) steady state, respectively. The volume of distribution was significantly different between the two groups (0.35 vs. 0.68 L/kg, p = < 0.0001). Highest frequency of target attainment (50-100 mcg/ml) occurred in the continuous infusion 2 mg/kg/h simulation for both critically ill (45.19%) and acutely ill (48.16%) groups., Discussion: Critically ill patients have an increased volume of distribution. Increasing the volume of distribution requires higher loading doses of VPA to obtain desired therapeutic concentrations. Continuous infusion VPA provides more consistent serum steady-state concentrations while mitigating pharmacokinetic variability.