Determining the Risk of Elevated Digoxin Concentrations Following Loading Dose in Patients With Acute and Chronic Kidney Disease.

BACKGROUND: The optimal loading dose of digoxin in patients with reduced kidney function is unknown. Tertiary references recommend reduced loading doses; however, these recommendations are based on immunoassays that are falsely elevated by the presence of digoxin-like immunoreactive substances, a problem that is minimized in modern assays. OBJECTIVE: To determine whether chronic kidney disease (CKD) or acute kidney injury (AKI) is associated with supratherapeutic digoxin concentrations after a digoxin loading dose. METHODS: A retrospective analysis on patients who received an intravenous loading dose of digoxin with a digoxin concentration collected 6 to 24 hours after the end of the dose. Patients were stratified into 3 groups: AKI, CKD, and non-AKI/CKD (NKI) based on glomerular filtration rate and serum creatinine. The primary outcome was frequency of supratherapeutic digoxin concentrations (>2 ng/mL) and secondary outcomes included frequency of adverse events. RESULTS: A total of 146 digoxin concentrations were included (AKI = 59, CKD = 16, NKI = 71). Frequencies of supratherapeutic concentrations were similar between groups (AKI: 10.2%, CKD: 18.8%, NKI: 11.3%; P = 0.61). Pre-planned logistic regression demonstrated no significant relationship between kidney function group and the development of a supratherapeutic concentration (AKI: odds ratio [OR]: 1.3, 95% confidence interval [CI]: 0.4-4.5; CKD: OR 4.3, 95% CI: 0.7-23). CONCLUSION AND RELEVANCE: This is the first study in routine clinical practice evaluating the relationship between kidney function and digoxin peak concentrations that differentiates AKI from CKD. We did not find a relationship between kidney function and peak concentrations; however, the group with CKD was underpowered.

Proposed guidance on cost-avoidance studies in pharmacy practice.

PURPOSE: Cost-avoidance studies of pharmacist interventions are common and often the first type of study conducted by investigators to quantify the economic impact of clinical pharmacy services. The purpose of this primer is to provide guidance for conducting cost-avoidance studies pertaining to clinical pharmacy practice. SUMMARY: Cost-avoidance studies represent a paradigm conceptually different from traditional pharmacoeconomic analysis. A cost-avoidance study reports on cost savings from a given intervention, where the savings is estimated based on a counterfactual scenario. Investigators need to determine what specifically would have happened to the patient if the intervention did not occur. This assessment can be fundamentally flawed, depending on underlying assumptions regarding the pharmacists' action and the patient trajectory. It requires careful identification of the potential consequence of nonaction, as well as probability and cost assessment. Given the uncertainty of assumptions, sensitivity analyses should be performed. A step-by-step methodology, formula for calculations, and best practice guidance is provided. CONCLUSIONS: Cost-avoidance studies focused on pharmacist interventions should be considered low-level evidence. These studies are acceptable to provide pilot data for the planning of future clinical trials. The guidance provided in this article should be followed to improve the quality and validity of such investigations.

Methods used to attribute costs avoided from pharmacist interventions in acute care: A scoping review.

PURPOSE: Cost-avoidance studies are common in pharmacy practice literature. This scoping review summarizes, critiques, and identifies current limitations of the methods that have been used to determine cost avoidance associated with pharmacists' interventions in acute care settings. METHODS: An Embase and MEDLINE search was conducted to identify studies that estimated cost avoidance from pharmacist interventions in acute care settings. We included studies with human participants and articles published in English from July 2010 to January 2021, with the intent of summarizing the evidence most relevant to contemporary practice. RESULTS: The database search retrieved 129 articles, of which 39 were included. Among these publications, less than half (18 of 39) mentioned whether the researchers assigned a probability for the occurrence of a harmful consequence in the absence of an intervention; thus, a 100% probability of a harmful consequence was assumed. Eleven of the 39 articles identified the specific harm that would occur in the absence of intervention. No clear methods of estimating cost avoidance could be identified for 7 studies. Among all 39 included articles, only 1 attributed both a probability to the potential harm and identified the cost specific to that harm. CONCLUSION: Cost-avoidance studies of pharmacists' interventions in acute care settings over the last decade have common flaws and provide estimates that are likely to be inflated. There is a need for guidance on consistent methodology for such investigations for reporting of results and to confirm the validity of their economic implications.

Acid-base effects of continuous infusion furosemide in clinically stable surgical ICU patients: an analysis based on the Stewart model.

OBJECTIVES: We sought to test the strength of correlation between predicted and observed systemic acid-base status based on the Stewart model equations during continuous infusion (CI) furosemide therapy. DESIGN, SETTING AND PARTICIPANTS: This was a prospective, single-center, observational study conducted in the Surgical ICU of a large academic medical center. Ten critically ill patients who received CI furosemide were included. MAIN OUTCOMES AND MEASURES: The primary purpose was to characterize the relationship between changes in serum electrolyte and acid-base status and the excretion of electrolytes in the urine during infusion of CI furosemide in critically ill patients. As a secondary endpoint, we sought to evaluate the predictive application of the Stewart model. Over 72-h, intake and output volumes, electrolyte content of fluids administered, plasma and urine electrolytes, urine pH, and venous blood gases were collected. Predicted and observed changes in acid-based status were compared for each day of diuretic therapy using Spearman's correlation coefficient. RESULTS: The mean (SD) strong ion difference (SID) increased from 45.2 (3.2) at baseline to 49.6 (4.0) after 72 h of continuous infusion furosemide. At Day 1, the mean SID (observed) (SD) was 47.5 (3.5) and the predicted SID was 49.5 (5.8). Day 1 observed plasma SID was positively correlated with the predicted SID (rs = 0.80, p = 0.01). By Days 2 and 3, the correlations of observed and predicted SID were no longer statistically significant. CONCLUSIONS AND RELEVANCE: Using the Stewart model, increases in SID as an indicator of metabolic alkalosis due to the chloruretic effects of furosemide were observed. Predicted and observed SID correlated well over the first 24 h of treatment.

Hydrochloric Acid Infusion for the Treatment of Metabolic Alkalosis in Surgical Intensive Care Unit Patients.

BACKGROUND: Older reports of use of hydrochloric acid (HCl) infusions for treatment of metabolic alkalosis document variable dosing strategies and risk. OBJECTIVES: This study sought to characterize use of HCl infusions in surgical intensive care unit patients for the treatment of metabolic alkalosis. METHODS: This retrospective review included patients who received a HCl infusion for >8 hours. The primary end point was to evaluate the utility of common acid-base equations for predicting HCl dose requirements. Secondary end points evaluated adverse effects, efficacy, duration of therapy, and total HCl dose needed to correct metabolic alkalosis. Data on demographics, potential causes of metabolic alkalosis, fluid volume, and duration of diuretics as well as laboratory data were collected. RESULTS: A total of 30 patients were included, and the average HCl infusion rate was 10.5 ± 3.7 mEq/h for an average of 29 ± 14.6 hours. Metabolic alkalosis was primarily diuretic-induced (n = 26). Efficacy was characterized by reduction in the median total serum CO2 from 34 to 27 mM/L ( P < 0.001). The change in chloride ion deficit and change in apparent strong ion difference (SIDa) were not correlated with total HCl administered. There were no documented serious adverse effects related to HCl infusions. CONCLUSION: HCl was effective for treating metabolic alkalosis, and no serious adverse events were seen. In this clinical setting, the baseline chloride ion deficit and SIDa were not useful for prediction of total HCl dose requirement, and serial monitoring of response is recommended.

Development of the Critical Care Pharmacotherapy Trials Network.

PURPOSE: The development of the Critical Care Pharmacotherapy Trials Network (CCPTN) as a model for practice-based pharmacotherapy research is described. SUMMARY: The CCPTN was formed in 2010 as a collaborative research network dedicated to scientific investigation in the field of critical care pharmacotherapy. The CCPTN organizational structure is consistent with many professional pharmacy and interdisciplinary organizations and organized into 3 primary domains: executive committee, working committees, and network membership. The network membership consists of critical care investigators dedicated to the mission and vision of the CCPTN and is open to anyone expressing an interest in contributing to high-level research. Network member sites represent the breadth of U.S. critical care practice environments. In addition, network members include individuals with demonstrated expertise in patient safety, administration, research design, grantsmanship, database management, peer review, and scientific writing. In 2015, there were more than 100 site investigators from around the United States and Canada. Projects to date have yielded numerous abstracts, platform presentations, and peer-reviewed publications in high-impact journals. The CCPTN has expanded to form collaborations with researchers in the United Kingdom, Australia, and New Zealand. The CCPTN has identified new potential partnerships and field-based areas for inquiry. Numerous opportunities for continued growth and scientific inquiry in the field of critical care pharmacotherapy research exist for the CCPTN to foster in the coming years. CONCLUSION: The CCPTN has been a successful model for practice-based pharmacotherapy research and assists its members in expanding critical care pharmacotherapy knowledge.

Relative bioavailability of orally administered fosphenytoin sodium injection compared with phenytoin sodium injection in healthy volunteers.

STUDY OBJECTIVE: To describe the pharmacokinetics of fosphenytoin (FPHT) sodium injection when administered orally, and to determine the relative oral bioavailability (FREL ) of FPHT sodium injection compared with PHT sodium injection based on pharmacokinetic modeling in healthy volunteers. DESIGN: Open-label, randomized, single-dose, two-period, two-sequence crossover study. SETTING: University-affiliated clinical research center funded by the National Center of Research Resources. SUBJECTS: Ten healthy adult volunteers. INTERVENTION: Subjects were randomized to receive a single oral dose of either PHT sodium injection or FPHT sodium injection at a dose equivalent to 400 mg PHT acid. Blood samples were collected at baseline (just prior to administration) and at 0.5, 1, 2, 4, 6, 12, 24, 48, and 72 hours after dose administration. After a 7-14-day washout period, the subjects underwent the same study procedures for administration of the other agent (PHT or FPHT). MEASUREMENTS AND MAIN RESULTS: The mean age and weight of the 10 subjects were 37 years and 72.5 kg, respectively, and the mean dose was 5.6 mg/kg based on PHT acid equivalence. The mean FREL of FPHT was 1.21 (95% confidence interval [CI] 1.07-1.35). Serum PHT concentrations were determined by fluorescence polarization immunoassay. The median (range) maximum serum concentration (Cmax ) values were significantly higher after FPHT administration compared with PHT: 10.7 (9.0-19.4) mg/L versus 5.0 (3.2-8.9) mg/L (p=0.002). The PHT concentration after oral administration of FPHT displayed faster absorption compared with PHT, with a median (range) time to reach Cmax of 1.0 (0.5-2.0) hours versus 6.0 (2.0-24.0) hours (p=0.008). All subjects completed the study without any serious adverse events reported. CONCLUSION: FPHT sodium injection given orally was absorbed more rapidly and to a significantly greater extent than PHT sodium injection given orally to healthy volunteers. Further evaluation of oral FPHT as an alternative in patients requiring enteral feedings is warranted.

Off-label use of gastrointestinal medications in the intensive care unit.

PURPOSE: Determine the level of evidence supporting off-label gastrointestinal (GI) medication use and identify the medication class and indication whereby off-label use was most common. MATERIALS AND METHODS: This prospective, multicentered observational study evaluated all medication orders written in 37 intensive care units (ICUs) in the United States, over a 24-hour period. All medications classified as "GI" according to a national reference were identified. The class and indication whereby off-label use was most prominent were determined and the level of evidence was described. RESULTS: There were 774 orders from 363 patients and 63% (489 of 774) were considered off-label. Proton pump inhibitors (PPIs) accounted for most of the off-label usage (55% [271 of 489]), followed by laxatives (16% [77 of 489]) and histamine-2-receptor antagonists (H2RAs; 15% [71 of 489]). When prescribed, 99% (271 of 274) of PPIs, 99% (71 of 72) of H2RAs, and 79% (30 of 38) of promotility agents were off-label. Stress ulcer prophylaxis (100% [309 of 309]), GI bleeding (100% [18 of 18]), and gastric motility (88% [30 of 34]) were the most common off-label indications. The most common strength of recommendation and level of evidence for off-label use was indeterminate (58% [282 of 489]) and none (57% [280 of 489]), respectively. CONCLUSION: The PPIs are the most widely used off-label medications in the ICU. Stress ulcer prophylaxis is the most common indication. The level of evidence supporting off-label GI medication use is poor.

Mathematical modeling to reduce waste of compounded sterile products in hospital pharmacies.

In recent years, many US hospitals embarked on "lean" projects to reduce waste. One advantage of the lean operational improvement methodology is that it relies on process observation by those engaged in the work and requires relatively little data. However, the thoughtful analysis of the data captured by operational systems allows the modeling of many potential process options. Such models permit the evaluation of likely waste reductions and financial savings before actual process changes are made. Thus the most promising options can be identified prospectively, change efforts targeted accordingly, and realistic targets set. This article provides one example of such a datadriven process redesign project focusing on waste reduction in an in-hospital pharmacy. A mathematical model of the medication prepared and delivered by the pharmacy is used to estimate the savings from several potential redesign options (rescheduling the start of production, scheduling multiple batches, or reordering production within a batch) as well as the impact of information system enhancements. The key finding is that mathematical modeling can indeed be a useful tool. In one hospital setting, it estimated that waste could be realistically reduced by around 50% by using several process changes and that the greatest benefit would be gained by rescheduling the start of production (for a single batch) away from the period when most order cancellations are made.

New dosing strategies for an old antibiotic: pharmacodynamics of front-loaded regimens of colistin at simulated pharmacokinetics in patients with kidney or liver disease.

Increasing evidence suggests that colistin monotherapy is suboptimal at currently recommended doses. We hypothesized that front-loading provides an improved dosing strategy for polymyxin antibiotics to maximize killing and minimize total exposure. Here, we utilized an in vitro pharmacodynamic model to examine the impact of front-loaded colistin regimens against a high bacterial density (10(8) CFU/ml) of Pseudomonas aeruginosa. The pharmacokinetics were simulated for patients with hepatic (half-life [t1/2] of 3.2 h) or renal (t1/2 of 14.8 h) disease. Front-loaded regimens (n=5) demonstrated improvement in bacterial killing, with reduced overall free drug areas under the concentration-time curve (fAUC) compared to those with traditional dosing regimens (n=14) with various dosing frequencies (every 12 h [q12h] and q24h). In the renal failure simulations, front-loaded regimens at lower exposures (fAUC of 143 mg · h/liter) obtained killing activity similar to that of traditional regimens (fAUC of 268 mg · h/liter), with an ∼97% reduction in the area under the viable count curve over 48 h. In hepatic failure simulations, front-loaded regimens yielded rapid initial killing by up to 7 log10 within 2 h, but considerable regrowth occurred for both front-loaded and traditional regimens. No regimen eradicated the high bacterial inoculum of P. aeruginosa. The current study, which utilizes an in vitro pharmacodynamic infection model, demonstrates the potential benefits of front-loading strategies for polymyxins simulating differential pharmacokinetics in patients with hepatic and renal failure at a range of doses. Our findings may have important clinical implications, as front-loading polymyxins as a part of a combination regimen may be a viable strategy for aggressive treatment of high-bacterial-burden infections.

Acute care clinical pharmacy practice: unit- versus service-based models.

This commentary from the 2010 Task Force on Acute Care Practice Model of the American College of Clinical Pharmacy was developed to compare and contrast the "unit-based" and "service-based" orientation of the clinical pharmacist within an acute care pharmacy practice model and to offer an informed opinion concerning which should be preferred. The clinical pharmacy practice model must facilitate patient-centered care and therefore must position the pharmacist to be an active member of the interprofessional team focused on providing high-quality pharmaceutical care to the patient. Although both models may have advantages and disadvantages, the most important distinction pertains to the patient care role of the clinical pharmacist. The unit-based pharmacist is often in a position of reacting to an established order or decision and frequently is focused on task-oriented clinical services. By definition, the service-based clinical pharmacist functions as a member of the interprofessional team. As a team member, the pharmacist proactively contributes to the decision-making process and the development of patient-centered care plans. The service-based orientation of the pharmacist is consistent with both the practice vision embraced by ACCP and its definition of clinical pharmacy. The task force strongly recommends that institutions pursue a service-based pharmacy practice model to optimally deploy their clinical pharmacists. Those who elect to adopt this recommendation will face challenges in overcoming several resource, technologic, regulatory, and accreditation barriers. However, such challenges must be confronted if clinical pharmacists are to contribute fully to achieving optimal patient outcomes.

The outcomes of emergency pharmacist participation during acute myocardial infarction.

BACKGROUND: Current guidelines recommend door-to-balloon times of 90 min or less for patients presenting to the emergency department (ED) with ST-segment elevation myocardial infarction (STEMI). OBJECTIVES: To determine if a clinical pharmacist for the ED (EPh) is associated with decreased door/diagnosis-to-cardiac catheterization laboratory (CCL) time and decreased door-to-balloon time. METHODS: A retrospective observational cohort study of ED patients with STEMI requiring urgent cardiac catheterization was conducted. Blinded data collection included timing of ED and CCL arrival, diagnostic electrocardiogram (ECG), and balloon angioplasty. For cases diagnosed after ED arrival, diagnosis time was substituted for door time. Diagnosis was the time ST elevations were evident on serial ECG. EPh present and not-present groups were compared. During the study period there were two EPhs and presence was determined by their scheduled time in the ED. Univariate and multivariate analyses was used to detect differences. RESULTS: Multivariate analysis of 120 patients, controlled for CCL staff presence and arrival by pre-hospital services, determined that EPh presence is associated with a mean 13.1-min (95% confidence interval [CI] 6.5-21.9) and 11.5-min (95% CI 3.9-21.5) decrease in door/diagnosis-to-CCL and door-to-balloon times, respectively. Patients were more likely to achieve a door/diagnosis-to-CCL time≤ 30 min (odds ratio [OR] 3.1, 95% CI 1.3-7.8) and≤ 45 min (OR 2.9, 95% CI-1.0, 8.5) and a door-to-balloon time≤ 90 min (OR 1.9, 95% CI 0.7-5.5) more likely when the EPh was present. CONCLUSIONS: EPh presence during STEMI presentation to the ED is independently associated with a decrease in door/diagnosis-to-CCL and door-to-balloon times.

Pharmacist-managed antimicrobial stewardship program for patients discharged from the emergency department.

Positive outcomes of antimicrobial stewardship programs in the inpatient setting are well documented, but the benefits for patients not admitted to the hospital remain less clear. This report describes a retrospective case-control study of patients discharged from the emergency department (ED) with subsequent positive cultures conducted to determine whether integrating antimicrobial stewardship responsibilities into practice of the emergency medicine clinical pharmacist (EPh) decreased times to positive culture follow-up, patient or primary care provider (PCP) notification, and appropriateness of antimicrobial therapy. Pre- and post-implementation groups of an EPh-managed antimicrobial stewardship program were compared. Positive cultures were identified in 177 patients, 104 and 73 in pre- and post-implementation groups, respectively. Median time to culture review in the pre-implementation group was 3 days (range 1-15) and 2 days (range 0-4) in the post-implementation group (P = .0001). There were 74 (71.2%) and 36 (49.3%) positive cultures that required notification in the pre- and post-implementation groups, respectively, and the median time to patient or PCP notification was 3 days (range 1-9) and 2 days (range 0-4) in the 2 groups (P = .01). No difference was seen in the appropriateness of therapy. In conclusion, EPh involvement reduced time to positive culture review and time to patient or PCP notification when indicated.

Interdisciplinary patient care in the intensive care unit: focus on the pharmacist.

The field of critical care medicine began to flourish only within the last 40 years, yet it provides some of the best examples of collaborative pharmacy practice models and evidence for the value of pharmacist involvement in interdisciplinary practice. This collaborative approach is fostered by critical care organizations that have elected pharmacists into leadership positions and recognized pharmacists through various honors. There is substantial literature to support the value of the critical care pharmacist as a member of an interdisciplinary intensive care unit (ICU) team, particularly in terms of patient safety. Furthermore, a number of economic investigations have demonstrated cost savings or cost avoidance with pharmacist involvement. As the published evidence supporting pharmacist involvement in patient care activities in the ICU setting has increased, surveys have demonstrated an increase in the percentage of pharmacists performing clinical activities. In addition, substantial support of pharmacists has been provided by other clinicians, safety officers, and administrative personnel who have been involved with the initiation and expansion of critical care pharmacy services in their own institutions. Although there is still room for improvement in the range of pharmacist involvement, particularly with respect to interdisciplinary activities related to education and scholarship, pharmacists have become essential members of interdisciplinary care teams in ICU settings.

Key articles and guidelines relative to intensive care unit pharmacotherapy: 2009 update.

Compilations of key articles and guidelines in a particular clinical practice area are useful not only to clinicians who practice in that area, but also to all clinicians. We compiled pertinent articles and guidelines pertaining to drug therapy in the intensive care setting from the perspective of experienced critical care pharmacists. A broad assembly of practitioners with expertise in various areas of intensive care unit pharmacology were involved in the compilation of this update.

A prospective evaluation of propylene glycol clearance and accumulation during continuous-infusion lorazepam in critically ill patients.

Propylene glycol is a commonly used diluent in several pharmaceutical preparations, including the sedative lorazepam. Fifty critically ill patients receiving continuous-infusion lorazepam for a minimum of 36 hours were prospectively evaluated to determine the extent of propylene glycol accumulation over time, characterize propylene glycol clearance in the presence of critical illness, and develop a pharmacokinetic model that would predict clearance based on patient-specific clinical, laboratory, and demographic factors. In this cohort, the median lorazepam infusion rate was 2.1 mg/h (0.5-18). Propylene glycol concentration correlated poorly with osmolality, osmol gap, and lactate. In all, 8 patients (16%) had significant propylene glycol accumulation (>25mg/dL). When propylene glycol concentrations were >25 mg/dL, the median lorazepam infusion rate before sample collection was higher, 6.4 (1.9-11.3) versus 2.0 (0.5-7.4) mg/h (P =.0003). A linear first-order model with interoccasion variability on clearance adjusted for total body weight and Acute Physiology and Chronic Health Evaluation II score predicted propylene glycol concentration.

Recommendations for end-of-life care in the intensive care unit: a consensus statement by the American College [corrected] of Critical Care Medicine.

BACKGROUND: These recommendations have been developed to improve the care of intensive care unit (ICU) patients during the dying process. The recommendations build on those published in 2003 and highlight recent developments in the field from a U.S. perspective. They do not use an evidence grading system because most of the recommendations are based on ethical and legal principles that are not derived from empirically based evidence. PRINCIPAL FINDINGS: Family-centered care, which emphasizes the importance of the social structure within which patients are embedded, has emerged as a comprehensive ideal for managing end-of-life care in the ICU. ICU clinicians should be competent in all aspects of this care, including the practical and ethical aspects of withdrawing different modalities of life-sustaining treatment and the use of sedatives, analgesics, and nonpharmacologic approaches to easing the suffering of the dying process. Several key ethical concepts play a foundational role in guiding end-of-life care, including the distinctions between withholding and withdrawing treatments, between actions of killing and allowing to die, and between consequences that are intended vs. those that are merely foreseen (the doctrine of double effect). Improved communication with the family has been shown to improve patient care and family outcomes. Other knowledge unique to end-of-life care includes principles for notifying families of a patient's death and compassionate approaches to discussing options for organ donation. End-of-life care continues even after the death of the patient, and ICUs should consider developing comprehensive bereavement programs to support both families and the needs of the clinical staff. Finally, a comprehensive agenda for improving end-of-life care in the ICU has been developed to guide research, quality improvement efforts, and educational curricula. CONCLUSIONS: End-of-life care is emerging as a comprehensive area of expertise in the ICU and demands the same high level of knowledge and competence as all other areas of ICU practice.