Emergency medicine pharmacist interventions reducing exposure to costs (EMPIRE-C).

INTRODUCTION: Emergency Medicine (EM) pharmacists are considered essential healthcare providers in the Emergency Department (ED). Limited data are available representing the types of interventions performed by ED pharmacists, especially in community-based health systems. METHODS: Retrospective, multi-centered, observational review of documented EM clinical pharmacist interventions into the electronic medical record (EMR) across five separate EDs between July 1, 2020 and June 30, 2021. Interventions were separated into three categories: ED Intervention, ED Outpatient Culture Review, and ED Discharge Antimicrobial Review. Interventions with supporting literature related to cost avoidance were also analyzed. RESULTS: A total of 23,794 interventions were logged by the EM pharmacy team between the three categories. Of those, 9181 were cost avoidance interventions resulting in $5,350,755.63 in total cost avoidance, or $582.81 per intervention. CONCLUSION: EM pharmacists practicing in community settings have a substantial impact on patients as evidenced by the large quantity and variety of interventions logged which also results in significant cost avoidance to the healthcare system.

Fixed-dose prothrombin complex concentrate for emergent warfarin reversal among patients with intracranial hemorrhage.

INTRODUCTION: Four-factor prothrombin complex concentrate (4PCC) is the preferred reversal agent for warfarin reversal, although the ideal dose is unknown. Fixed-dose 4PCC offers simplified dosing compared to standard-dosing algorithms with potentially lower risks of thromboembolic complications given lower doses are typically utilized. METHODS: Retrospective, observational, multicentered, pre- post- study of patients who received 4PCC for warfarin reversal among four hospitals within the same regional health system. Standard-dose patients received variable doses ranging from 25 to 50 units/kg based on total body weight and initial INR and fixed-dose patients received 2000 units. The primary outcome was achievement of a target INR ≤ 1.4 on the first post-4PCC INR result. RESULTS: After exclusions, 48 and 42 patients were analyzed in the standard-dose and fixed-dose groups, respectively. There was no difference in the ability to achieve a target INR of ≤1.4 (82.6% vs 81.5%, p = 0.14). Both groups received the same median dose of 2000 units, although fixed-dose patients actually received a higher weight-based dose than standard-dose patients (27 units/kg vs 24.5 units/kg). CONCLUSION: A fixed-dose 4PCC regimen of 2000 units among patients with ICH was as effective as standard-dose 4PCC for INR reversal among patients with ICH. However, fixed-doses of 2000 units at times exceeded standard 4PCC doses which may be contradictory to the goals of fixed-dose 4PCC for warfarin reversal.

Urinary tract infection pocket card effect on preferred antimicrobial prescribing for cystitis among patients discharged from the emergency department.

PURPOSE: To evaluate the impact of a urinary tract infection (UTI) pocket card on preferred antibiotic prescribing for patients discharged from the emergency department (ED) with a diagnosis of cystitis. METHODS: A multicenter, retrospective, pre-post study was conducted to compare outcomes following the introduction of a UTI pocket card. The primary outcome was prescribing rates for institutional first-line preferred antibiotics (cephalexin and nitrofurantoin) versus other antimicrobials for cystitis. Secondary outcomes included prescriber adherence to recommended therapy in regards to discharge dose, frequency, duration, and healthcare utilization rates. RESULTS: The study included 915 patients in total, 407 in the preintervention group and 508 in the postintervention group. The frequency of preferred antibiotic prescribing was significantly increased after the introduction of a UTI pocket card compared to prior to its introduction (81.7% vs 72.0%, P = 0.001). Significant increases in prescribing of an appropriate antibiotic dose (78.0% vs 66.8%, P < 0.0001) and frequency (64.2% vs 47.4%, P < 0.0001) were also found post intervention. No significant differences were seen between the pre- and postintervention groups with regards to healthcare utilization rates. CONCLUSION: A UTI pocket card increased preferred antibiotic prescribing for cystitis in the ED. This study provides data on a successful antimicrobial stewardship intervention in the ED setting.

Time to antibiotic administration: Sepsis alerts called in emergency department versus in the field via emergency medical services.

INTRODUCTION: The Severe Sepsis and Septic Shock Early Management Bundle (SEP-1) identifies patients with "severe sepsis" and mandates antibiotics within a specific time window. Rapid time to administration of antibiotics may improve patient outcomes. The goal of this investigation was to compare time to antibiotic administration when sepsis alerts are called in the emergency department (ED) with those called in the field by emergency medical services (EMS). METHODS: This was a multi-center, retrospective review of patients designated as sepsis alerts in ED or via EMS in the field, presenting to four community emergency departments over a six-month period. RESULTS: 507 patients were included, 419 in the ED alert group and 88 in the field alert group. Mean time to antibiotic administration was significantly faster in the field alert group when compared to the ED alert group (48.5 min vs 64.5 min, p < 0.001). Patients were more likely to receive antibiotics within 60 min of ED arrival in the field alert group (59.1% vs 44%, p = 0.01). Secondary outcomes including mortality, hospital length of stay, intensive care unit length of stay, sepsis diagnosis on admission, Clostridioides difficile infection rates, fluid bolus utilization, anti-MRSA antibiotic utilization rates, and anti-Pseudomonal antibiotic utilization rates were not found to be significantly different. CONCLUSIONS: Sepsis alerts called in the field via EMS may decrease time to antibiotics and increase the likelihood of antibiotic administration occurring within 60 min of arrival when compared to those called in the ED.

Multi-centered evaluation of a novel fixed-dose four-factor prothrombin complex concentrate protocol for warfarin reversal.

INTRODUCTION: Previous studies have shown fixed-dose 4PCC to be as effective as standard-dose 4PCC for warfarin reversal. However, certain patient populations such as those with high total body weight (TBW) or elevated baseline INR may be at increased risk for treatment failure. The purpose of this study was to validate the efficacy of a novel fixed-dose 4PCC protocol for warfarin reversal. METHODS: This was a multi-centered observational comparison of patients who received 4PCC for warfarin reversal. Fixed-dose patients received 1500 units of 4PCC with the dose increased to 2000 units in patients with a baseline INR ≥ 7.5, a TBW ≥ 100 kg, or for intracranial hemorrhage (ICH). Standard-dosing followed manufacturer recommendations. The primary outcome was achievement of a post-4PCC INR of ≤1.4. Secondary outcomes included target INR achievement among patients with a baseline INR ≥ 7.5, a TBW ≥ 100 kg, or neurologic bleeding indications; hospital length of stay; cost of therapy; and thromboembolic complications. RESULTS: A total of 116 patients were included in the standard-dose group and 75 in the fixed-dose group. There was no difference in the primary outcome (65% vs 57%, p = 0.32). There was no difference in secondary outcomes aside from cost of therapy in which fixed-dose 4PCC was less expensive than standard-dose 4PCC. CONCLUSION: A fixed-dose 4PCC regimen for warfarin reversal of 1500 units, with an increased dose of 2000 units for select patients, is as effective as standard-dose 4PCC for INR reversal.

Emergent Warfarin Reversal With Fixed-Dose 4-Factor Prothrombin Complex Concentrate.

BACKGROUND: Four-factor prothrombin complex concentrate (4FPCC) is used for emergent warfarin reversal, but dosing remains controversial. Following approval, further studies have evaluated a variety of fixed-dose regimens. The studies utilized lower doses as compared with package insert dosing and provided data in regard to efficacy, safety, and cost savings. Further data are needed, however, to determine which fixed-dose regimen provides optimal efficacy and safety for emergent warfarin reversal. OBJECTIVES: The purpose of this study is to evaluate the efficacy, safety, and cost-savings of a fixed-dose 4FPCC protocol. METHODS: This multicentered, retrospective chart review of adult patients requiring 4FPCC for emergent warfarin reversal utilized a fixed-dose regimen of 1500 units. The 2 primary outcomes were the proportion of patients who achieved a post-4FPCC international normalized ratio (INR) of ≤1.5 and ≤2. Secondary outcomes included thrombotic events within 7 days of 4FPCC administration and survival to discharge. A cost analysis was also performed to identify potential cost savings. RESULTS: Of the 64 patients included, 44 (68.8%) achieved a post-4FPCC INR ≤1.5, and 61 (95.3%) achieved a post-4FPCC INR ≤2.0. No thrombotic events were reported; 55 (85.9%) patients survived to hospital discharge. More than $1000 was saved per patient via utilization of the fixed-dose protocol. CONCLUSION AND RELEVANCE: A fixed-dose of 1500 units of 4FPCC successfully achieved a target INR of ≤1.5 in the majority of patients and resulted in no thrombotic events. This study adds to the data evaluating alternative 4FPCC dosing regimens in comparison to package insert recommended dosing.

Hemodynamic Effects of Propofol for Induction of Rapid Sequence Intubation in Traumatically Injured Patients.

Present guidelines for emergency intubation in traumatically injured patients recommend rapid sequence intubation (RSI) as the preferred method of airway management but specific pharmacologic agents for RSI remain controversial. To evaluate hemodynamic differences between propofol and other induction agents when used for RSI in trauma patients. Single-center, retrospective review of trauma patients intubated in the emergency department. Patients were divided in two groups based on induction agent, propofol or nonpropofol. The primary outcome was incidence of hypotension within 30 minutes of intubation. Secondary outcomes included hospital length of stay and inhospital mortality. The study protocol was approved by the Institutional Review Board. Of the 744 patients identified, 83 were analyzed, 43 in the propofol group and 40 in the nonpropofol group. Groups were similar at baseline in terms of pre-RSI hemodynamics, injury mechanism, initial Glasgow Coma Score, and Injury Severity Score. On univariate analysis, although not statistically significant, postintubation hypotension was more common in patients who received propofol compared with those who did not, 39.5 per cent versus 22.5 per cent (P = 0.9). When adjusted for age, Injury Severity Score, and pre-RSI hemodynamics, the risk of hypotension among propofol-treated patients was significantly higher (OR = 3.64; 95% Confidence interval 1.16-13.24). There were no significant differences between groups in hospital length of stay or mortality. Propofol increases the odds of postintubation hypotension in traumatically injured patients. Considerable caution should be used when contemplating the use of propofol the for induction of injured patients requiring RSI because other agents possess more favorable hemodynamic profiles.

Development of recommendations for dosing of commonly prescribed medications in critically ill obese children.

PURPOSE: The development and use of a decision support tool to help formulate recommendations for dosing of commonly prescribed medications in critically ill obese children are described. METHODS: Medications prescribed in 2010 to critically ill infants and children (younger than 18 years) were identified from the Pediatric Health Information System. The most commonly prescribed and therapeutically monitored medications were extracted. Supportive evidence for obesity dosing was identified through a standardized computerized search involving medical subject heading terminology and age filters using PubMed and Ovid. A usefulness scoring system was developed to rate the strength and applicability of the literature to critically ill obese children. A decision supporttool was then created to aid in the formulation of a dosing weight for each medication based on the usefulness score, published pharmacokinetic properties, clinical studies available in the primary literature, and consideration of clinical consequences of underdosing or overdosing. RESULTS: A total of 113 medications were evaluated, and 122 discrete citations, supporting 66 medications, were reviewed. Seventy-two percent of citations had general obesity dosing information, and 13% had pediatric-specific information. The overall mean usefulness score was 5.1±4.7 (median, 7). The decision support tool was incorporated to make final dosing weight recommendations for obese children. Ultimately, total body weight was recommended for 52 medications, adjusted weight for 43 medications, and ideal body weight for 18 medications. CONCLUSION: The inadequacy of obesity dosing information for most medications commonly ordered for children admitted to a pediatric intensive care unit led to the development of a decision support tool to aid in formulating dosing recommendations.

Gene Composer in a structural genomics environment.

The structural genomics effort at the Seattle Structural Genomics Center for Infectious Disease (SSGCID) requires the manipulation of large numbers of amino-acid sequences and the underlying DNA sequences which are to be cloned into expression vectors. To improve efficiency in high-throughput protein structure determination, a database software package, Gene Composer, has been developed which facilitates the information-rich design of protein constructs and their underlying gene sequences. With its modular workflow design and numerous graphical user interfaces, Gene Composer enables researchers to perform all common bioinformatics steps used in modern structure-guided protein engineering and synthetic gene engineering. An example of the structure determination of H1N1 RNA-dependent RNA polymerase PB2 subunit is given.

The Protein Maker: an automated system for high-throughput parallel purification.

The Protein Maker is an automated purification system developed by Emerald BioSystems for high-throughput parallel purification of proteins and antibodies. This instrument allows multiple load, wash and elution buffers to be used in parallel along independent lines for up to 24 individual samples. To demonstrate its utility, its use in the purification of five recombinant PB2 C-terminal domains from various subtypes of the influenza A virus is described. Three of these constructs crystallized and one diffracted X-rays to sufficient resolution for structure determination and deposition in the Protein Data Bank. Methods for screening lysis buffers for a cytochrome P450 from a pathogenic fungus prior to upscaling expression and purification are also described. The Protein Maker has become a valuable asset within the Seattle Structural Genomics Center for Infectious Disease (SSGCID) and hence is a potentially valuable tool for a variety of high-throughput protein-purification applications.

Gene composer: database software for protein construct design, codon engineering, and gene synthesis.

BACKGROUND: To improve efficiency in high throughput protein structure determination, we have developed a database software package, Gene Composer, which facilitates the information-rich design of protein constructs and their codon engineered synthetic gene sequences. With its modular workflow design and numerous graphical user interfaces, Gene Composer enables researchers to perform all common bio-informatics steps used in modern structure guided protein engineering and synthetic gene engineering. RESULTS: An interactive Alignment Viewer allows the researcher to simultaneously visualize sequence conservation in the context of known protein secondary structure, ligand contacts, water contacts, crystal contacts, B-factors, solvent accessible area, residue property type and several other useful property views. The Construct Design Module enables the facile design of novel protein constructs with altered N- and C-termini, internal insertions or deletions, point mutations, and desired affinity tags. The modifications can be combined and permuted into multiple protein constructs, and then virtually cloned in silico into defined expression vectors. The Gene Design Module uses a protein-to-gene algorithm that automates the back-translation of a protein amino acid sequence into a codon engineered nucleic acid gene sequence according to a selected codon usage table with minimal codon usage threshold, defined G:C% content, and desired sequence features achieved through synonymous codon selection that is optimized for the intended expression system. The gene-to-oligo algorithm of the Gene Design Module plans out all of the required overlapping oligonucleotides and mutagenic primers needed to synthesize the desired gene constructs by PCR, and for physically cloning them into selected vectors by the most popular subcloning strategies. CONCLUSION: We present a complete description of Gene Composer functionality, and an efficient PCR-based synthetic gene assembly procedure with mis-match specific endonuclease error correction in combination with PIPE cloning. In a sister manuscript we present data on how Gene Composer designed genes and protein constructs can result in improved protein production for structural studies.

Combined protein construct and synthetic gene engineering for heterologous protein expression and crystallization using Gene Composer.

BACKGROUND: With the goal of improving yield and success rates of heterologous protein production for structural studies we have developed the database and algorithm software package Gene Composer. This freely available electronic tool facilitates the information-rich design of protein constructs and their engineered synthetic gene sequences, as detailed in the accompanying manuscript. RESULTS: In this report, we compare heterologous protein expression levels from native sequences to that of codon engineered synthetic gene constructs designed by Gene Composer. A test set of proteins including a human kinase (P38alpha), viral polymerase (HCV NS5B), and bacterial structural protein (FtsZ) were expressed in both E. coli and a cell-free wheat germ translation system. We also compare the protein expression levels in E. coli for a set of 11 different proteins with greatly varied G:C content and codon bias. CONCLUSION: The results consistently demonstrate that protein yields from codon engineered Gene Composer designs are as good as or better than those achieved from the synonymous native genes. Moreover, structure guided N- and C-terminal deletion constructs designed with the aid of Gene Composer can lead to greater success in gene to structure work as exemplified by the X-ray crystallographic structure determination of FtsZ from Bacillus subtilis. These results validate the Gene Composer algorithms, and suggest that using a combination of synthetic gene and protein construct engineering tools can improve the economics of gene to structure research.

The plug-based nanovolume Microcapillary Protein Crystallization System (MPCS).

The Microcapillary Protein Crystallization System (MPCS) embodies a new semi-automated plug-based crystallization technology which enables nanolitre-volume screening of crystallization conditions in a plasticware format that allows crystals to be easily removed for traditional cryoprotection and X-ray diffraction data collection. Protein crystals grown in these plastic devices can be directly subjected to in situ X-ray diffraction studies. The MPCS integrates the formulation of crystallization cocktails with the preparation of the crystallization experiments. Within microfluidic Teflon tubing or the microfluidic circuitry of a plastic CrystalCard, approximately 10-20 nl volume droplets are generated, each representing a microbatch-style crystallization experiment with a different chemical composition. The entire protein sample is utilized in crystallization experiments. Sparse-matrix screening and chemical gradient screening can be combined in one comprehensive ;hybrid' crystallization trial. The technology lends itself well to optimization by high-granularity gradient screening using optimization reagents such as precipitation agents, ligands or cryoprotectants.