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Background: Modern medical care increasingly requires coordinated teamwork and communication between healthcare professionals of different disciplines. Unfortunately, healthcare professional students are rarely afforded the opportunity to learn effective methods of interprofessional (IP) communication and teamwork strategies during their education. The question of how to best incorporate IP interactions in the curricula of the schools of health professions remains unanswered.Objective: We aim to solve the lack of IP education in the pharmacy curricula through the use of high fidelity simulation (HFS) to allow teams of medical, pharmacy, nursing, physician assistant, and social work students to work together in a controlled environment to solve cases of complex medical and social issues.Methods: Once weekly for a 4-week time period, students worked together to complete complex simulation scenarios in small IP teams consisting of pharmacy, medical, nursing, social work, and physician assistant students. Student perception of the use of HFS was evaluated by a survey given at the conclusion of the HFS sessions. Team communication was evaluated through the use of Communication and Teamwork Skills (CATS) Assessment by 2 independent evaluators external to the project.Results: The CATS scores improved from the HFS sessions 1 to 2 (p = 0.01), 2 to 3 (p = 0.035), and overall from 1 to 4 (p = 0.001). The inter-rater reliability between evaluators was high (0.85, 95% CI 0.71, 0.99). Students perceived the HFS improved: their ability to communicate with other professionals (median =4); confidence in patient care in an IP team (median=4). It also stimulated student interest in IP work (median=4.5), and was an efficient use of student time (median=4.5)Conclusion: The use of HFS improved student teamwork and communication and was an accepted teaching modality. This method of exposing students of the health sciences to IP care should be incorporated throughout the curricula.

Background: Pharmacovigilance algorithms are used to assess the likelihood of adverse drug reaction (ADR) occurrence. The preferred instrument for use in the intensive care unit (ICU) is not established.Objective: The primary objective of this study was to compare the agreement between the Kramer algorithm, Naranjo criteria and Jones algorithm for the evaluation of ADRs in the ICU. A secondary objective was to compare the agreement between the same pharmacovigilance algorithms for ADR determination when applied in a retrospective versus concurrent fashion in the ICU.Study Design: There were two phases in this study. Phase I was the retrospective evaluation (i.e. after the patient was discharged from the hospital) conducted in patients admitted during July 2005 to June 2006. Phase II was the concurrent phase (i.e. while the patient was in the hospital) conducted over 6 weeks in 2008. Both phases were conducted at the University of Pittsburgh Medical Center and included adult patients admitted to the medical ICU.Intervention: In phase I, a random sample of 261 medication signals were evaluated individually for potential ADRs using the Kramer algorithm, Naranjo criteria and Jones algorithm. In phase II, an active medication monitoring system was used to detect five abnormal laboratory values, resulting in a random sample of 253 signals that were evaluated using the same three algorithms.Main Outcome Measure: Percentage agreement among the algorithms for all levels of causality was estimated using a kappa statistic for both phases of the study.Results: For phase I, the kappa values were all >0.7 ranging from 0.721 to 0.855 between instruments, with Naranjo versus Kramer having the highest kappa, which is considered excellent agreement. The kappa statistic between individual instruments for phase II are <0.7 ranging from 0.423 to 0.635, which is considered moderate agreement, with Naranjo versus Jones displaying the lowest kappa while still exhibiting moderate agreement. For phase II, the Kramer algorithm had better agreement with both the Naranjo criteria and the Jones algorithm.Conclusions: These instruments demonstrated similar results for evaluating ADRs in the ICU retrospectively, suggesting that instrument selection with any of the three instruments is reasonable. For concurrent ADR evaluations, there is greater variability in the level of causality obtained among pharmacovigilance algorithms and Kramer displayed better agreement with its comparators. A suggestion for a more definitive concurrent ADR assessment is to use more than one algorithm. This may be challenging in daily clinical practice; however, it is a reasonable expectation for research. [ABSTRACT FROM AUTHOR]

Objectives: An evaluation of risk factors for adverse drug events in critically ill patients has not been previously studied. The purpose of this original study was to determine risk factors for adverse drug events in critically ill adult patients.Design: This retrospective case-control study includes patients who were admitted to the intensive care unit during a 7.5-yr period.Setting: Academic medical center with 647 beds that contains approximately 120 intensive care unit beds.Patients: Patients in the case group experienced an adverse drug event as documented in the hospital's database. The control group comprised the next two patients admitted to the same intensive care unit by the same admitting service.Interventions: None.Measurements and Main Results: Twenty-nine suspected risk factors identified from the literature were evaluated, including patient characteristics, drug characteristics, and laboratory values using a multiple logistic regression. A sample of 1101 cases and controls (54% male), with a mean age of 59.4 ± 17.5 yrs, were identified. In 367 cases, there was a total of 499 documented adverse drug events. Patients with kidney injury, thrombocytopenia, and those admitted emergently were 16-times, 3-times, and 2-times more likely to have an adverse drug event, respectively. Patients who were administered intravenous medications had a 3% higher risk of having an adverse drug event for each drug dispensed. Overall, the case group received more drugs per intensive care unit day and more drugs per intensive care unit stay.Conclusions: Several patient and drug-related characteristics contribute to the risk of adverse drug events in critically ill patients. Diligent monitoring of factors that can influence the pharmacokinetic properties for existing drug therapies is necessary. Drug regimens should be evaluated daily for minimization. Based on previous studies, pharmacists as part of the interdisciplinary team could help to manage these risks. [ABSTRACT FROM AUTHOR]

Background: Mortality and morbidity are increased in patients experiencing drug-drug interactions. Unfortunately, there is a paucity of literature describing clinically significant drug-drug interactions occurring in the intensive care unit (ICU). Knowing the clinically significant drug-drug interactions allows the opportunity for prevention through knowledge and computer-assisted programmes.Objective: To identify significant potential drug-drug interactions occurring in the cardiovascular ICU (CCU) and the cardiothoracic ICU (CTICU).Study Design: Prospective, observational study conducted over a total of 8 weeks in February and March 2009.Setting: CCU and CTICU in a major academic medical centre (Presbyterian Hospital, University of Pittsburgh Medical Centre).Patients: All adult patients (>or=18 years of age) admitted during 1 month in each ICU.Intervention: Micromedex and Lexi-Interact interaction databases were used to screen each patient's medication profile daily for the presence of potentially interacting drug pairs that would be considered a potential drug-drug interaction. A severity assessment using these databases was completed after a potential drug-drug interaction was identified.Primary Outcome Measure: The frequency of significant drug-drug interactions, including those that were considered major or contraindicated, according to two commercially available interaction databases.Results: Evaluations of 400 patient medication profiles were conducted, resulting in 225 profiles possessing one or more potential drug-drug interactions. A total of 1150 potential interactions were identified, resulting in 287.5 potential interactions per 100 patient-days. Of the 1150 potential drug-drug interactions, 458 were unique interacting drug pairs; 5-9% of the potential interactions were considered major or contraindicated. Many of the significant and frequent potential interactions involved blood coagulation modifiers, potential interactions that could result in QTc prolongation, and cytochrome P450 inhibition. Micromedex and Lexi-Interact agreed on the severity ratings in 20.5% of the potential interactions.Conclusions: Significant potential drug-drug interactions occur in the CCU and CTICU, highlighting the need for active surveillance to potentially prevent patient harm. Clinicians should also consider using two references for identifying interactions, due to the lack of congruence between sources. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To compare survival rates of patients with in-hospital cardiac arrest due to pulseless ventricular tachycardia/ventricular fibrillation treated with lidocaine, amiodarone, or amiodarone plus lidocaine. DESIGN: Multicenter retrospective medical record review. SETTING: Three academic medical centers in the United States. PATIENTS: Hospitalized adult patients who received amiodarone, lidocaine, or a combination for pulseless ventricular tachycardia/ventricular fibrillation between August 1, 2000, and July 31, 2002. MEASUREMENTS AND MAIN RESULTS: Data were collected according to the Utstein style. In-hospital proportion of patients living at 24 hrs and discharge were analyzed using chi-square analysis. Of the 605 patient medical records reviewed, 194 met criteria for inclusion (n=79 for lidocaine, n=74 for amiodarone, n=41 for combination). Available data showed no difference in proportion of patients alive 24 hrs post-cardiac arrest (p=.39). Cox regression analysis indicated a decreased likelihood of survival in patients with pulseless ventricular tachycardia/ventricular fibrillation as an initial rhythm as compared with those who presented with bradycardia followed by pulseless ventricular tachycardia/ventricular fibrillation and in those patients who received amiodarone as compared with lidocaine. However, only 14 patients (25%) in the amiodarone group received the recommended initial 300-mg intravenous bolus, and amiodarone was administered an average of 8 mins later in the code compared with lidocaine (p<.001). CONCLUSIONS: These results generate the hypothesis that inpatients with cardiac arrest may have different benefits from lidocaine and amiodarone than previously demonstrated. Inadequate dosing and later administration of amiodarone in the code were two confounding factors in this study. Prospective studies evaluating these agents are warranted. [ABSTRACT FROM AUTHOR]

Purpose: To characterize trajectories of nephrotoxic potential (NxP) drug use among older adults with Type 2 Diabetes (T2D) treated with SGLT2is and identify associated patient characteristics., Methods: Using 2012-2019 Medicare data, we selected patients with T2D who filled at least one prescription for SGLT2is. Index date was the date of the first SGLT2i prescription filled. We quantified the number of drugs with NxP used every month during the first 12 months following the index date. The monthly counts of drugs with NxP were incorporated into the group-based trajectory model to identify groups with similar drug use patterns. Finally, we performed a multinomial logistic regression model to examine the association between patient characteristics and group membership., Results: The study cohort comprised 8811 Medicare beneficiaries with T2D who initiated SGLT2i during the study period with the mean age 67.5 ± 10.6 years. We identified 3 trajectories NxP drug use: no (n = 2142, 24%), low (n = 4752, 54%) and high (n = 1917, 22%) use of drugs with NxP, with patients falling into these categories based on the number of drugs with NxP they used over the time: no drugs, one drug, or two or more drugs. Age, gender, low-income subsidy eligibility and clinical characteristics were associated with group membership., Conclusions: We successfully identified three trajectory groups, with a substantial proportion of patients showing low use of drugs with NxP. Both social and clinical factors were associated with the use of NxP drugs., (© 2025 John Wiley & Sons Ltd.)

Data addressing safety concerns related to potential drug interactions between cannabis-derived products and pharmaceutical medications in the pediatric population are lacking. In this study, we retrieved case reports through a published literature search using PubMed and spontaneous reporting data using the Food and Drug Administration's Adverse Event Reporting System (FAERS) to identify potential cannabis- and cannabinoid-drug interactions in individuals younger than 18 years old. To evaluate the published case reports, we used the Drug Interaction Probability Scale (DIPS), a 10-item questionnaire designed to discern the causal relationship between a potential drug interaction and adverse drug reactions (ADRs). FAERS reports were deduplicated and analyzed to gather information regarding patient demographics, associated drugs, nature of the ADRs, outcomes, professions of the reporters, and reporting timelines. Seven published case reports and 9142 FAERS ADRs reports were included in the final analysis. Based on the findings, caution is warranted when cannabis or cannabinoids are used in combination with prescribed medications, including methadone, everolimus, fluoxetine, and paroxetine. Cannabinoids may inhibit drug-metabolizing enzymes, including several cytochrome P450s, leading to increased drug exposure and potentially, an increased risk for ADRs., (© 2024 The Author(s). Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.)

The increasing utilization of cannabis products combined with lack of data regarding potential cannabis-prescription drug interactions is concerning. This study aimed to review published case reports and FDA Adverse Event Reporting System (FAERS) spontaneous reports to assess cannabis-drug interactions in persons aged 18 and over. A literature search identified 20 case reports that were each assessed for drug interaction causality using the Drug Interaction Probability Scale. Data collected from the FAERS revealed a greater proportion of reports mentioning serious outcomes, including death, when cannabis was used concomitantly with controlled substances compared to noncontrolled substances. Fisher's exact test showed a statistically significant difference between the controlled and noncontrolled groups (p = 0.043). Overall, these findings emphasize the need for additional research and vigilant monitoring of cannabis use when combined with other medications., (© 2024 The Author(s). Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.)

Purpose of Review: Despite advances in critical care medicine, the incidence of clinically important upper gastrointestinal bleeding (UGIB) remains consistent. One therapy that reduces UGIB is the use of stress ulcer prophylaxis (SUP). In the past year, several key manuscripts have been published regarding SUP, providing updated recommendations for its prescription. In this review, we provide commentary on these recommendations and areas for future research., Recent Findings: Risk factors for UGIB include chronic liver disease, coagulopathy, severe neurologic illness or injury, and shock. The prescription of SUP is associated with a decreased occurrence of UGIB but no benefit in mortality. Although both histamine-2 receptor antagonists and proton pump inhibitors (PPIs) are recommended for SUP, it is possible that PPIs may be associated with increased mortality in critically ill patients. The short-term use of SUP is not expected to be associated with most adverse drug events, but inappropriate continuation of SUP increases this risk., Summary: Patient-specific considerations based on recent data help with improving the prescription of SUP, although additional research is necessary. The use of artificial intelligence may be able to predict at risk patients with the potential to influence appropriate prescription of SUP and reduce the occurrence of UGIB., (Copyright © 2025 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose of Review: The aim of this review is to provide a discussion of new perspectives for up-to-date definitions, a contemporary classification system, and the potential role of stress and damage biomarkers in the context of drug related kidney diseases and disorders., Recent Findings: Acute kidney disease (AKD) is a term recently introduced in the literature describing an abnormality in kidney structure and function that lasts for less than 3 months. Drugs in the context of AKD is described as a new perspective; referred to as drug induced AKD. A framework that includes drugs into the 2X2 classification schema for acute kidney injury (AKI) is provided. Finally, stress and damage biomarkers are examined to assess risk of drug associated AKI (D-AKI), differentiate which drugs cause AKI, differentiate drugs from other etiologies and assess the prognosis of D-AKI., Summary: Consistent definitions should be adopted with consideration to drug related diseases and disorders. Drug management can be guided using novel biomarkers to isolate a possible drug cause in the presence of more than one nephrotoxin or a nondrug cause, assisting with the diagnosis of pseudo-AKI, and deciding the likelihood AKI recovery. Furthermore, stress and damage kidney biomarkers provide the opportunity to detect subclinical AKI for early intervention in patients at high-risk for severe AKI., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: The objective was to explore and describe the role of pharmacists in providing postdischarge care to patients with kidney disease., Data Sources: PubMed, Embase (Elsevier), CINAHL (Ebscohost), Web of Science Core Collection, and Scopus were searched on January 30, 2023. Publication date limits were not included. Search terms were identified based on 3 concepts: kidney disease, pharmacy services, and patient discharge. Experimental, quasi-experimental, observational, and qualitative studies, or study protocols, describing the pharmacist's role in providing postdischarge care for patients with kidney disease, excluding kidney transplant recipients, were eligible., Study Selection and Data Extraction: Six unique interventions were described in 10 studies meeting inclusion criteria., Data Synthesis: Four interventions targeted patients with acute kidney injury (AKI) during hospitalization and 2 evaluated patients with pre-existing chronic kidney disease. Pharmacists were a multidisciplinary care team (MDCT) member in 5 interventions and were the sole provider in 1. Roles commonly identified include medication review, medication reconciliation, medication action plan formation, kidney function assessment, drug dose adjustments, and disease education. Some studies showed improvements in diagnostic coding, laboratory monitoring, medication therapy problem (MTP) resolution, and patient education; prevention of hospital readmission was inconsistent. Limitations include lack of standardized reporting of kidney disease, transitions of care processes, and differences in outcomes evaluated., Relevance to Patient Care and Clinical Practice: This review identifies potential roles of a pharmacist as part of a postdischarge MDCT for patients with varying degrees of kidney disease., Conclusions: The pharmacist's role in providing postdischarge care to patients with kidney disease is inconsistent. Multidisciplinary care teams including a pharmacist provided consistent identification and resolution of MTPs, improved patient education, and increased self-awareness of diagnosis., Competing Interests: Declaration of Conflicting InterestsThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: MMM, JWS, JBR, JLW, RM, and EO have nothing to disclose. EFB is supported by a grant from the National Institute of Allergy and Infectious Diseases (K23AI143882). The funding source had no role in this manuscript and its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. Consulting relationship with Wolters-Kluwer. SKG is supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases R01DK121730 and U01DK130010, the National Center for Complementary and Integrative Health U54AT008909, and the Jewish Healthcare Foundation. SKG holds an executive position in the Society of Critical Care Medicine. The content of this manuscript is solely the responsibility of the author and does not represent the official views of the Society of Critical Care Medicine. EDS Personal fees for service on the editorial board for the Clinical Journal of the American Society of Nephrology, royalties as an author for UptoDate, and consulting agreement with Novartis Pharmaceutics for DSMB service. SAS discloses the following speaking fees from Baxter Canada, consulting from AstraZeneca, and honorarium from Otsuka and Novo Nordisk. JAN is supported by grants from NIDDK (R01DK128208, R01DK133539, U01DK12998, and U54DK137307).

Background: Accurately estimating glomerular filtration rate (GFR) is crucial for dosing medications in hospitalized patients. Due to limitations of serum creatinine for GFR estimation, serum cystatin C (CysC) has been explored as an alternative functional kidney biomarker. This study assessed discordance between eGFR Cr and eGFR CysC in a large sample of hospitalized patients and examined the frequency of renally eliminated medications affected by eGFR discordance., Methods: This multisite historical study included adults hospitalized between 2011 and 2023 with CysC and serum creatinine reported within 24 h of each other. The first concurrent biomarker pair for each patient was analyzed. eGFR discordance and use of renally eliminated medications were described., Results: 17,718 hospitalized patients with concurrent creatinine and CysC assessments were included. The median eGFR Cr was 65 mL/min, and the eGFR CysC was 46 mL/min. The median absolute difference of eGFR Cr -eGFR CysC was 15 mL/min, and 7972 patients (45%) had a > 30% absolute difference. There was a significantly greater percentage of patients with an eGFR <30 mL/min based on eGFR CysC (26%) compared to eGFR Cr (15%) (p < 0.001). Patients were prescribed an average of 20 medications in the 24 h surrounding the concurrent biomarker assessment. Renally eliminated medications accounted for 39% ± 13% of medication orders, and 80% of patients with eGFR discordance were prescribed five or more renally eliminated medications., Conclusion: Substantial eGFR discordance between eGFR CysC and eGFR Cr was observed in hospitalized patients, which directly affects the dosing of renally eliminated medications. Further research is needed to optimize the pharmacotherapy of renally eliminated medications with discordant GFR assessments to improve medication safety and effectiveness., (© 2024 Pharmacotherapy Publications, Inc.)

Background: Implementation of evidence-based guidelines in patient care is inefficient. Only 14% of new research are routinely adopted into clinical practice. The atrial fibrillation (AF) practice guidelines recommend anticoagulation in men with a CHA 2 DS 2 -VASc score greater than or equal to 2 and in women with a CHA 2 DS 2 -VASc score greater than or equal to 3. Despite these recommendations, oral anticoagulation prescribing rates were found to be as low as 51%. Existing frameworks, such as the Theoretical Domain Framework (TDF), are used in implementation science to identify behavior changes to overcome barriers to guideline adoption., Objective: In this project, we explored behavioral themes and barriers that prevented clinician adherence to evidence-based recommendations for patients with non-valvular atrial fibrillation (NVAF) and developed interventions to overcome those barriers., Methods: Nine focused interviews were conducted with stakeholders across multiple disciplines involved with NVAF care. Interview questions were based on the TDF and designed to determine behavior changes necessary to increase appropriate anticoagulation prescribing and decrease unnecessary NVAF hospital admissions. The interviews were transcribed and coded using NVivo 12 qualitative data analysis software (released 2018). Themes were documented, and interventions were then developed to address the barriers., Results: TDF interviews yielded 4 main barrier themes regarding appropriate NVAF management in 2 theoretical domains. These themes were lack of knowledge, cost of anticoagulation, patient refusal to take anticoagulation, and social determinants of health. The theoretical domains were knowledge and environmental context and resources., Conclusion and Relevance: Based on our limited interviews, the TDF framework informed potential barriers contributing to the underutilization of appropriate anticoagulation in patients with NVAF. Techniques for behavior change interventions may be applied to overcome the identified barriers., Competing Interests: Declaration of Conflicting InterestsThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: JC was a consultant to the Pfizer-Bristol Myers Squibb Alliance. CM is a current employee of Pfizer, Inc. NA was a former employee of Pfizer, Inc.

Purpose: The goals of this paper are to (1) provide evidence and expert consensus to support a unified approach to estimating kidney filtration in adults with stable kidney function using race-free estimated glomerular filtration rate (eGFR) in place of Cockcroft-Gault estimated creatinine clearance (C-G eCrCL) for medical and medication-related decisions, and (2) demonstrate how adjusting eGFR results for an individual's body surface area (BSA) when it is higher or lower than 1.73 m2 will improve results for medication-related decisions., Summary: C-G eCrCL is predominantly used by US pharmacists to determine eGFR for the purposes of medication-related decisions, even though more accurate eGFR equations exist. Several driving factors make it the ideal time to shift clinical practice from using C-G eCrCL to eGFR. These factors include the following: (1) 2024 Food and Drug Administration (FDA) guidance for industry recommends eGFR over C-G eCrCL to evaluate the impact on pharmacokinetics in patients with impaired kidney function; (2) a joint National Kidney Foundation (NKF) and American Society of Nephrology task force recommends 3 race-free Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) eGFR equations for medical and medication-related decision-making; (3) the almost ubiquitous use of standardized serum creatinine assay methods in US clinical laboratories; and (4) increasing availability and use of serum cystatin C for eGFR assessment. This publication guides practitioners through the rationale for using race-free eGFR equations for medication-related decisions and how to implement this practice change., Conclusion: The NKF Workgroup for Implementation of Race-Free eGFR-Based Medication-Related Decisions suggests that health systems, health settings, clinical laboratories, electronic health record systems, compendia and data vendors, and healthcare practitioners involved with medication-related decision-making transition away from C-G eCrCL and towards the race-free eGFR equations for more accurate assessment of kidney filtration and consistency in medication and medical decision-making across the US., (© American Society of Health-System Pharmacists 2024. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

There is a scarcity of information related to the financial impact of acute kidney injury (AKI), and even more so the economics of drug-associated AKI (D-AKI). Our goal was to provide a comprehensive summary of the economic burden of D-AKI by evaluating the costs of D-AKI compared to not developing AKI and cost savings associated with nephrotoxin stewardship approaches. Following the PRISMA guidelines, a literature search was conducted using PubMed to identify articles from database inception through November 2023. The main outcomes included AKI incidence, resource use, and cost of nephrotoxin stewardship programs/D-AKI event or no event. Key findings were summarized based on whether the study compared the cost of D-AKI vs. no AKI or identified potential cost savings associated with a nephrotoxin stewardship method to prevent D-AKI or worsening D-AKI. All costs were adjusted to USD2023. Twenty-five studies met the inclusion criteria. Eight studies compared the cost of D-AKI to no AKI. Total admission costs of patients who developed D-AKI ranged from $47,696 to $173,569. Nineteen studies implemented nephrotoxin stewardship with 12 substituting a less nephrotoxic drug; five using therapeutic drug monitoring and two altering drug dosing to limit exposure. Overall, these prevention strategies ranged from $5,171 to $364,973 in total medical cost savings and $17 to $942 in total cost savings per patient-day. The in-hospital economic impact of D-AKI is substantial. Implementing nephrotoxin stewardship strategies to reduce D-AKI is associated with cost savings. Institutions should adopt strategic and efficient nephrotoxin stewardship programs to optimize patient care and reduce costs., (© 2024 The Author(s). Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Nephrotoxicity is one of the most common complications of vancomycin use in clinical practice. Silymarin has potential to be a renoprotective agent for nephrotoxic drugs due to its antioxidant, anti-inflammatory, and anti-apoptotic effects. The aim of this clinical study is evaluating the potential effects of silymarin on preventing vancomycin nephrotoxicity. A multicenter, randomized, double-blinded, placebo-controlled, clinical trial was conducted on patients with the indication of systemic vancomycin for at least 7 days. Patients were screened daily and those who met the inclusion criteria were selected and randomly assigned into either silymarin or placebo groups. Accordingly, 140 mg silymarin tablet (Livergol®) or placebo was given orally three times daily. Silymarin or placebo were provided in conjunction with vancomycin for at least 7 days. If vancomycin therapy was extended beyond 7 days, the administration of silymarin or placebo was continued until the end of vancomycin treatment. Malondialdehyde, glutathione, and total antioxidant capacity were measured in the serum on days 0 and 7. A trough level of vancomycin was assessed 30 min before the fifth dose of vancomycin. Acute kidney injury (AKI) was monitored in each patient daily during the course of vancomycin treatment. The causality assessment of all identified cases of vancomycin associated AKI was performed by the Naranjo scale. The primary endpoint was vancomycin nephrotoxicity. It was defined based on the KDIGO 2012 criteria for AKI as either an increase of 0.3 units or more in serum creatinine level during 48 h or 50% (1.5-fold) or more during 7 days compared to baseline values. During the study period, 34 patients in the silymarin group and 32 patients in the placebo group completed the clinical trial. Demographic, baseline clinical, and laboratory characteristics were comparable between placebo and silymarin groups. The number of patients with AKI on days 5, 6, 7, 11,12, 13, and 14 in the placebo group was significantly higher than that in the silymarin group (p-value < 0.05). The incidence of acute tubular injury on the day  5 and 7 of vancomycin treatment was significantly lower in the silymarin group (p-value = 0.005 and p-value = 0.032, respectively). Antioxidant indexes including serum total antioxidant capacity and glutathione significantly increased in the silymarin group (p-value < 0.001 for both indexes). In contrast, serum malondialdehyde as an end product of lipid peroxidation pathway significantly decreased in the silymarin group during 7 days (p-value < 0.001). The results of the present pilot, clinical trial suggested that silymarin co-administration may prevent vancomycin nephrotoxicity., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The objective of this project was to develop a standardized list of renally eliminated and potentially nephrotoxic drugs that will help inform initiatives to improve medication safety. Several available lists of medications from the published literature including original research articles and reviews, and from regulatory agencies, tertiary references, and clinical decision support systems were compiled, consolidated, and compared. Only systemically administered medications were included. Medication combinations were included if at least 1 active ingredient was considered renally dosed or potentially nephrotoxic. The medication list was reviewed for completeness and clinical appropriateness by a multidisciplinary team of individuals with expertise in critical care, nephrology, and pharmacy. An initial list of renally dosed and nephrotoxic drugs was created. After reconciliation and consensus from clinical experts, a standardized list of 681 drugs is proposed. The proposed evidence-based standardized list of renally dosed and potentially nephrotoxic drugs will be useful to harmonize epidemiologic and medication quality improvement studies. In addition, the list can be used for clinical purposes with surveillance in nephrotoxin stewardship programs. We suggest an iterative re-evaluation of the list with emerging literature and new medications on an approximately annual basis., Competing Interests: Declaration of Conflicting InterestsThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: EFB consults for Wolters-Kluwer and Baxter Healthcare, which are unrelated to this work. All other authors declare that they have no competing interests or relevant conflicts of interest to disclose.

Patients with cirrhosis are prone to developing acute kidney injury (AKI), a complication associated with a markedly increased in-hospital morbidity and mortality, along with a risk of progression to chronic kidney disease. Whereas patients with cirrhosis are at increased risk of developing any phenotype of AKI, hepatorenal syndrome (HRS), a specific form of AKI (HRS-AKI) in patients with advanced cirrhosis and ascites, carries an especially high mortality risk. Early recognition of HRS-AKI is crucial since administration of splanchnic vasoconstrictors may reverse the AKI and serve as a bridge to liver transplantation, the only curative option. In 2023, a joint meeting of the International Club of Ascites (ICA) and the Acute Disease Quality Initiative (ADQI) was convened to develop new diagnostic criteria for HRS-AKI, to provide graded recommendations for the work-up, management and post-discharge follow-up of patients with cirrhosis and AKI, and to highlight priorities for further research., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Disease-modifying anti-rheumatic drugs (DMARDs), since their introduction in 1990, have revolutionized the management of rheumatoid arthritis. Newer DMARDs have recently been approved, influencing treatment patterns and clinical guidelines., Objective: To update the current prescribing patterns of DMARDs in the pharmacotherapy of rheumatoid arthritis (RA) to include the pandemic era., Methods: This was a retrospective cross-sectional multi-year study. Using Optum's Clinformatics® Data Mart Database, we summarized trends in the prevalence of DMARD use in the USA from 2016 to 2021 by year for adult patients ≥ 18 years old with at least one medical RA claim and one pharmacy/medical claim of a DMARD medication. Trends included type of DMARD, class of DMARD (conventional (csDMARDs), biologics [tumor necrosis factor (TNFi) and Non-TNFi), and Janus kinase inhibitors (JAKs)], and triple therapy [methotrexate (MTX), hydroxychloroquine (HCQ), sulfasalazine (SUL)] used., Results: The total sample from 2016 to 2021 was 670,679 commercially insured patients. The average age was 63.7 years (SD 13.6), and 76.7% were female and 70% were White. csDMARDs remain the most prescribed (ranging from 77.2 to 79.2%). Although JAKs were the least prescribed DMARD class, their proportion more than doubled from 2016 (1.5%) to 2021 (4%). MTX utilization declined from 40% in 2016 to 34% in 2021. In contrast, HCQ use increased during the pandemic era from < 25% in 2018 to 30% in 2021. Although there is evidence of the therapeutic benefit of triple therapy, its use was very low (~ 1%) compared to biologics only (~ 17%) or biologics+MTX (~ 10%)., Conclusion: About half of patients with RA were on DMARDs. As expected, csDMARDs were highly used consistently. The COVID-19 pandemic might have influenced the use of HCQ and infusion DMARDs. Triple therapy use remains low., (© 2024. The Author(s).)

Importance: β-lactam (BL) allergies are the most common drug allergy worldwide, but most are reported in error. BL allergies are also well-established risk factors for adverse drug events and antibiotic-resistant infections during inpatient health care encounters, but the understanding of the long-term outcomes of patients with BL allergies remains limited., Objective: To evaluate the long-term clinical outcomes of patients with BL allergies., Design, Setting, and Participants: This longitudinal retrospective cohort study was conducted at a single regional health care system in western Pennsylvania. Electronic health records were analyzed for patients who had an index encounter with a diagnosis of sepsis, pneumonia, or urinary tract infection between 2007 and 2008. Patients were followed-up until death or the end of 2018. Data analysis was performed from January 2022 to January 2024., Exposure: The presence of any BL class antibiotic in the allergy section of a patient's electronic health record, evaluated at the earliest occurring observed health care encounter., Main Outcomes and Measures: The primary outcome was all-cause mortality, derived from the Social Security Death Index. Secondary outcomes were defined using laboratory and microbiology results and included infection with methicillin-resistant Staphylococcus aureus (MRSA), Clostridium difficile, or vancomycin-resistant Enterococcus (VRE) and severity and occurrence of acute kidney injury (AKI). Generalized estimating equations with a patient-level panel variable and time exposure offset were used to evaluate the odds of occurrence of each outcome between allergy groups., Results: A total of 20 092 patients (mean [SD] age, 62.9 [19.7] years; 12 231 female [60.9%]), of whom 4211 (21.0%) had BL documented allergy and 15 881 (79.0%) did not, met the inclusion criteria. A total of 3513 patients (17.5%) were Black, 15 358 (76.4%) were White, and 1221 (6.0%) were another race. Using generalized estimating equations, documented BL allergies were not significantly associated with the odds of mortality (odds ratio [OR], 1.02; 95% CI, 0.96-1.09). BL allergies were associated with increased odds of MRSA infection (OR, 1.44; 95% CI, 1.36-1.53), VRE infection (OR, 1.18; 95% CI, 1.05-1.32), and the pooled rate of the 3 evaluated antibiotic-resistant infections (OR, 1.33; 95% CI, 1.30-1.36) but were not associated with C difficile infection (OR, 1.04; 95% CI, 0.94-1.16), stage 2 and 3 AKI (OR, 1.02; 95% CI, 0.96-1.10), or stage 3 AKI (OR, 1.06; 95% CI, 0.98-1.14)., Conclusions and Relevance: Documented BL allergies were not associated with the long-term odds of mortality but were associated with antibiotic-resistant infections. Health systems should emphasize accurate allergy documentation and reduce unnecessary BL avoidance.

Introduction: Acute kidney injury (AKI) is a common complication of sepsis associated with increased risk of death. Preclinical data and observational human studies suggest that activation of AMP-activated protein kinase, an ubiquitous master regulator of energy that can limit mitochondrial injury, with metformin may protect against sepsis-associated AKI (SA-AKI) and mortality. The Randomized Clinical Trial of the Safety and FeasibiLity of Metformin as a Treatment for sepsis-associated AKI (LiMiT AKI) aims to evaluate the safety and feasibility of enteral metformin in patients with sepsis at risk of developing SA-AKI., Methods and Analysis: Blind, randomised, placebo-controlled clinical trial in a single-centre, quaternary teaching hospital in the USA. We will enrol adult patients (18 years of age or older) within 48 hours of meeting Sepsis-3 criteria, admitted to intensive care unit, with oral or enteral access. Patients will be randomised 1:1:1 to low-dose metformin (500 mg two times per day), high-dose metformin (1000 mg two times per day) or placebo for 5 days. Primary safety outcome will be the proportion of metformin-associated serious adverse events. Feasibility assessment will be based on acceptability by patients and clinicians, and by enrolment rate., Ethics and Dissemination: This study has been approved by the Institutional Review Board. All patients or surrogates will provide written consent prior to enrolment and any study intervention. Metformin is a widely available, inexpensive medication with a long track record for safety, which if effective would be accessible and easy to deploy. We describe the study methods using the Standard Protocol Items for Randomized Trials framework and discuss key design features and methodological decisions. LiMiT AKI will investigate the feasibility and safety of metformin in critically ill patients with sepsis at risk of SA-AKI, in preparation for a future large-scale efficacy study. Main results will be published as soon as available after final analysis., Trial Registration Number: NCT05900284., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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.

Acute kidney injury (AKI), which is a common complication of acute illnesses, affects the health of individuals in community, acute care and post-acute care settings. Although the recognition, prevention and management of AKI has advanced over the past decades, its incidence and related morbidity, mortality and health care burden remain overwhelming. The rapid growth of digital technologies has provided a new platform to improve patient care, and reports show demonstrable benefits in care processes and, in some instances, in patient outcomes. However, despite great progress, the potential benefits of using digital technology to manage AKI has not yet been fully explored or implemented in clinical practice. Digital health studies in AKI have shown variable evidence of benefits, and the digital divide means that access to digital technologies is not equitable. Upstream research and development costs, limited stakeholder participation and acceptance, and poor scalability of digital health solutions have hindered their widespread implementation and use. Here, we provide recommendations from the Acute Disease Quality Initiative consensus meeting, which involved experts in adult and paediatric nephrology, critical care, pharmacy and data science, at which the use of digital health for risk prediction, prevention, identification and management of AKI and its consequences was discussed., (© 2023. Springer Nature Limited.)

Purpose of Review: Drug associated kidney injury (D-AKI) occurs in 19-26% of hospitalized patients and ranks as the third to fifth leading cause of acute kidney injury (AKI) in the intensive care unit (ICU). Given the high use of antimicrobials in the ICU and the emergence of new resistant organisms, the implementation of preventive measures to reduce the incidence of D-AKI has become increasingly important., Recent Findings: Artificial intelligence is showcasing its capabilities in early recognition of at-risk patients for acquiring AKI. Furthermore, novel synthetic medications and formulations have demonstrated reduced nephrotoxicity compared to their traditional counterparts in animal models and/or limited clinical evaluations, offering promise in the prevention of D-AKI. Nephroprotective antioxidant agents have had limited translation from animal studies to clinical practice. The control of modifiable risk factors remains pivotal in avoiding D-AKI., Summary: The use of both old and new antimicrobials is increasingly important in combating the rise of resistant organisms. Advances in technology, such as artificial intelligence, and alternative formulations of traditional antimicrobials offer promise in reducing the incidence of D-AKI, while antioxidant medications may aid in minimizing nephrotoxicity. However, maintaining haemodynamic stability using isotonic fluids, drug monitoring, and reducing nephrotoxic burden combined with vigilant antimicrobial stewardship remain the core preventive measures for mitigating D-AKI while optimizing effective antimicrobial therapy., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Drug-induced kidney disease (DIKD) accounts for about one-fourth of all cases of acute kidney injury (AKI) in hospitalized patients, especially in critically ill setting. There is no standard definition or classification system of DIKD. To address this, a phenotype definition of DIKD using expert consensus was introduced in 2015. Recently, a novel framework for DIKD classification was proposed that incorporated functional change and tissue damage biomarkers. Medications were stratified into four categories, including "dysfunction without damage," "damage without dysfunction," "both dysfunction and damage," and "neither dysfunction nor damage" using this novel framework along with predominant mechanism(s) of nephrotoxicity for drugs and drug classes. Here, we briefly describe mechanisms and provide examples of drugs/drug classes related to the categories in the proposed framework. In addition, the possible movement of a patient's kidney disease between certain categories in specific conditions is considered. Finally, opportunities and barriers to adoption of this framework for DIKD classification in real clinical practice are discussed. This new classification system allows congruencies for DIKD with the proposed categorization of AKI, offering clarity as well as consistency for clinicians and researchers., (© 2023. The Author(s).)

Purpose: Significant increases in the volume of preprint articles due to the COVID-19 pandemic, we examined the reliability of preprint articles compared to their peer-reviewed publications., Materials and Methods: Preprint articles evaluating experimental studies of select treatment options (anticoagulation, dexamethasone, hydroxychloroquine, remdesivir, and tocilizumab) for COVID-19 in the critically ill, available in a peer-reviewed publication were screened for inclusion within Altmetric (n = 2040). A total of 40 articles met inclusion criteria, with 21 being randomly selected for evaluation. The primary outcome of this evaluation was a change in a study's reported primary outcome or statistical significance between preprint and peer-reviewed articles. Secondary outcomes included changes in primary/secondary outcome effect size and change in study conclusion., Results: One article (4.8%, 95% CI 0.12%-23.8%) had a change in the primary outcome. Seven articles (33.3%, 95% CI 14.6%-57.0%) had a change in the primary outcome's effect measure. Five studies (23.8%, 95% CI 8.2%-47.2%) had changes in statistical significance of at least one secondary outcome. Four studies (19.0%, 95% CI 5.4%-41.9%) had a change in study conclusion., Conclusions: In preprint articles of COVID-19 treatments, the provided primary outcome is generally reliable, while interpretation of secondary outcomes should be made with caution, while awaiting completion of the peer-review process., 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.

Importance: Despite hydroxyurea being an established treatment for sickle cell disease (SCD), it remains underused. The recent approval of the disease-modifying treatments (DMTs) l-glutamine, crizanlizumab, and voxelotor underscores the need to understand the uptake of DMTs in the current treatment landscape., Objective: To explore characteristics that may be associated with DMT use and to describe observed patterns of yearly DMT use from 2014 to 2021., Design, Setting, and Participants: This cross-sectional study used administrative claims data from Optum's deidentified Clinformatics Data Mart Database from January 1, 2014, to September 30, 2021, to identify adults and children with SCD. Data were analyzed from August 1, 2022, to August 28, 2023., Exposure: Use of DMTs., Main Outcomes and Measures: Patient characteristics across groups with varying patterns of DMT use and yearly patterns of prescription fills for hydroxyurea, crizanlizumab, voxelotor, and l-glutamine., Results: A total of 5022 beneficiaries with SCD (2081 [41.4%] aged 18-45 years; 2929 [58.3%] female) were included in sample A (144 [2.9%] inconsistent users, 274 [5.5%] incident users, 892 [17.8%] consistent users, and 3712 [73.9%] non-DMT users). Inconsistent users had a higher prevalence of vaso-occlusive crises (mean [SD], 3.7 [4.7]), splenic complications (6 of 144 [4.2%]), pulmonary complications (36 of 144 [25.0%]), kidney disease (21 of 144 [14.6%]), acute chest syndrome (18 of 144 [12.5%]), and health care visits (eg, mean [SD] inpatient visits, 7.0 [10.7]) compared with the other use groups. Non-DMT users had the lowest prevalence of vaso-occlusive crises (mean [SD], 0.8 [2.4]), acute chest syndrome (109 of 3712 [2.9%]), and inpatient (mean [SD], 2.0 [6.6]) and emergency department (mean [SD], 0.7 [3.1]) visits and the highest proportion of adults 65 years and older (593 of 3712 [16.0%]). In sample B (6387 beneficiaries with SCD), hydroxyurea use modestly increased from 428 of 2188 participants (19.6%) in 2014 to 701 of 2880 (24.3%) in 2021. Use of l-glutamine increased briefly but gradually decreased throughout the study period. In 2021, out of 2880 participants, 102 (3.5%) had at least 1 fill for crizanlizumab and 131 (4.6%) had at least 1 fill for voxelotor. Overall, total DMT use increased from 428 of 2188 participants (19.6%) in 2014 to 815 of 2880 patients (28.3%) in 2021., Conclusions and Relevance: In this cross-sectional analysis of adults and children with SCD, uptake of DMTs remained low from 2014 to 2021, despite the approval of newer therapies. Notable differences in patient characteristics across varied DMT exposure types necessitate further exploration into factors that facilitate DMT use and the creation of strategies to enhance DMT uptake.

Background: There is a lack of understanding of the barriers reported by healthcare providers when evaluating beta-lactam allergies, but knowledge of these barriers is required for practical and effective implementation interventions., Methods: Twenty-five healthcare providers, consisting of physicians, nurses and pharmacists practicing in the areas of intensive care, emergency medicine, infectious disease and general hospital practice, were interviewed between September 2021 and July 2023. Twenty-three of these providers were practising in the USA. A semi-structured interview guide grounded in the Theoretical Domain Framework was used for the interviews. Deductive and inductive analysis was performed on the interview transcripts, and translated into intervention recommendations using the Behaviour Change Wheel., Results: Widely held beliefs included a lack of clear policy for the evaluation of allergies, confusing or missing documentation of allergy information, confidence in their own and their colleagues' ability to evaluate allergies when information is available, and pharmacists as the provider most equipped to evaluate beta-lactam allergies., Conclusions: Health systems should adopt and disseminate policies for the evaluation of beta-lactam allergies, and promote the use of pharmacists in the evaluation of drug allergies when possible. Allergy sections of electronic health records should be reworked to encourage unambiguous documentation of allergy reactions and support using previously tolerated beta-lactam antibiotics., (Copyright © 2023 The Healthcare Infection Society. Published by Elsevier Ltd. All rights reserved.)

Competing Interests: Dr. Kane-Gill holds an executive position and received funding from the Society of Critical Care Medicine, received grant funding from the National Institute of Diabetes and Digestive and Kidney Diseases (R01DK121730 and U01DK130010), the National Center for Complementary and Integrative Health (U54AT008909), she received support for article research from the National Institutes of Health; and the Jewish Healthcare Foundation. The remaining authors have disclosed that they do not have any potential conflicts of interest.

Background: Acute kidney injury is a common postoperative complication affecting between 10% and 30% of surgical patients. Acute kidney injury is associated with increased resource usage and chronic kidney disease development, with more severe acute kidney injury suggesting more aggressive deterioration in clinical outcomes and mortality., Methods: We considered 42,906 surgical patients admitted to University of Florida Health (n = 51,806) between 2014 and 2021. Acute kidney injury stages were determined using the Kidney Disease Improving Global Outcomes serum creatinine criteria. We developed a recurrent neural network-based model to continuously predict acute kidney injury risk and state in the following 24 hours and compared it with logistic regression, random forest, and multi-layer perceptron models. We used medications, laboratory and vital measurements, and derived features from past one-year records as inputs. We analyzed the proposed model with integrated gradients for enhanced explainability., Results: Postoperative acute kidney injury at any stage developed in 20% (10,664) of the cohort. The recurrent neural network model was more accurate in predicting nearly all categories of next-day acute kidney injury stages (including the no acute kidney injury group). The area under the receiver operating curve and 95% confidence intervals for recurrent neural network and logistic regression models were for no acute kidney injury (0.98 [0.98-0.98] vs 0.93 [0.93-0.93]), stage 1 (0.95 [0.95-0.95] vs. 0.81 [0.80-0.82]), stage 2/3 (0.99 [0.99-0.99] vs 0.96 [0.96-0.97]), and stage 3 with renal replacement therapy (1.0 [1.0-1.0] vs 1.0 [1.0-1.0]., Conclusion: The proposed model demonstrates that temporal processing of patient information can lead to more granular and dynamic modeling of acute kidney injury status and result in more continuous and accurate acute kidney injury prediction. We showcase the integrated gradients framework's utility as a mechanism for enhancing model explainability, potentially facilitating clinical trust for future implementation., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objectives: Clinical decision support systems (CDSSs) are used in various aspects of healthcare to improve clinical decision-making, including in the ICU. However, there is growing evidence that CDSS are not used to their full potential, often resulting in alert fatigue which has been associated with patient harm. Clinicians in the ICU may be more vulnerable to desensitization of alerts than clinicians in less urgent parts of the hospital. We evaluated facilitators and barriers to appropriate CDSS interaction and provide methods to improve currently available CDSS in the ICU., Design: Sequential explanatory mixed-methods study design, using the BEhavior and Acceptance fRamework., Setting: International survey study., Patient/subjects: Clinicians (pharmacists, physicians) identified via survey, with recent experience with clinical decision support., Interventions: An initial survey was developed to evaluate clinician perspectives on their interactions with CDSS. A subsequent in-depth interview was developed to further evaluate clinician (pharmacist, physician) beliefs and behaviors about CDSS. These interviews were then qualitatively analyzed to determine themes of facilitators and barriers with CDSS interactions., Measurements and Main Results: A total of 48 respondents completed the initial survey (estimated response rate 15.5%). The majority believed that responding to CDSS alerts was part of their job (75%) but felt they experienced alert fatigue (56.5%). In the qualitative analysis, a total of five facilitators (patient safety, ease of response, specificity, prioritization, and feedback) and four barriers (excess quantity, work environment, difficulty in response, and irrelevance) were identified from the in-depth interviews., Conclusions: In this mixed-methods survey, we identified areas that institutions should focus on to improve appropriate clinician interactions with CDSS, specific to the ICU. Tailoring of CDSS to the ICU may lead to improvement in CDSS and subsequent improved patient safety outcomes., Competing Interests: Dr. Bates reports grants and personal fees from EarlySense, personal fees from Center for Digital Innovation Negev, equity from ValeraHealth, equity from Clew, equity from MDClone, personal fees and equity from AESOP, personal fees and equity from Feelbetter, equity from Guided Clinical Solutions, and grants from International Business Machines Corporation Watson Health, outside the submitted work. Dr. Bates has a patent pending (PHC-028564 US Patent Cooperation Treaty), on intraoperative clinical decision support. Dr. Kane-Gill receives grant funding from the National Institute of Diabetes and Digestive and Kidney Diseases R01DK121730 and U01DK130010, the National Center for Complementary and Integrative Health U54AT008909, and the Jewish Healthcare Foundation. Drs. Sorce and Kane-Gill also hold executive positions in the Society of Critical Care Medicine. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2023 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Background: AKI is associated with mortality in patients hospitalized with coronavirus disease 2019 (COVID-19); however, its incidence, geographic distribution, and temporal trends since the start of the pandemic are understudied., Methods: Electronic health record data were obtained from 53 health systems in the United States in the National COVID Cohort Collaborative. We selected hospitalized adults diagnosed with COVID-19 between March 6, 2020, and January 6, 2022. AKI was determined with serum creatinine and diagnosis codes. Time was divided into 16-week periods (P1-6) and geographical regions into Northeast, Midwest, South, and West. Multivariable models were used to analyze the risk factors for AKI or mortality., Results: Of a total cohort of 336,473, 129,176 (38%) patients had AKI. Fifty-six thousand three hundred and twenty-two (17%) lacked a diagnosis code but had AKI based on the change in serum creatinine. Similar to patients coded for AKI, these patients had higher mortality compared with those without AKI. The incidence of AKI was highest in P1 (47%; 23,097/48,947), lower in P2 (37%; 12,102/32,513), and relatively stable thereafter. Compared with the Midwest, the Northeast, South, and West had higher adjusted odds of AKI in P1. Subsequently, the South and West regions continued to have the highest relative AKI odds. In multivariable models, AKI defined by either serum creatinine or diagnostic code and the severity of AKI was associated with mortality., Conclusions: The incidence and distribution of COVID-19-associated AKI changed since the first wave of the pandemic in the United States., Podcast: This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/CJASN/2023&#95;08&#95;08&#95;CJN0000000000000192.mp3., (Copyright © 2023 by the American Society of Nephrology.)

Introduction: Nephrotoxin exposure is significantly associated with acute kidney injury (AKI) development. A standardized list of nephrotoxic medications to surveil and their perceived nephrotoxic potential (NxP) does not exist for non-critically ill patients., Objective: This study generated consensus on the nephrotoxic effect of 195 medications used in the non-intensive care setting., Methods: Potentially nephrotoxic medications were identified through a comprehensive literature search, and 29 participants with nephrology or pharmacist expertise were identified. The primary outcome was NxP by consensus. Participants rated each drug on a scale of 0-3 (not nephrotoxic to definite nephrotoxicity). Group consensus was met if ≥ 75% of responses were one single rating or a combination of two consecutive ratings. If ≥ 50% of responses indicated "unknown" or not used in the non-intensive care setting, the medication was removed for consideration. Medications not meeting consensus for a given round were included in the subsequent round(s)., Results: A total of 191 medications were identified in the literature, with 4 medications added after the first round from participants' recommendations. NxP index rating consensus after three rounds was: 14 (7.2%) no NxP in almost all situations (rating 0); 62 (31.8%) unlikely/possibly nephrotoxic (rating 0.5); 21 (10.8%) possibly nephrotoxic (rating 1); 49 (25.1%) possibly/probably nephrotoxic (rating 1.5); 2 (1.0%) probably nephrotoxic (rating 2); 8 (4.1%) probably/definite nephrotoxic (rating 2.5); 0 (0.0%) definitely nephrotoxic (rating 3); and 39 (20.0%) medications were removed from consideration., Conclusions: NxP index rating provides clinical consensus on perceived nephrotoxic medications in the non-intensive care setting and homogeneity for future clinical evaluations and research., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Objective: Between 2012 and 2017, the U.S. Food and Drug Administration (FDA) approved 10 antidiabetic indicated therapies. Due to the limited literature on voluntarily reported safety outcomes for recently approved antidiabetic drugs, this study investigated adverse drug reactions (ADRs) reported in the FDA Adverse Event Reporting System (FAERS)., Research Design and Methods: A disproportionality analysis of spontaneously reported ADRs was conducted. FAERS reports from January 1, 2012 to March 31, 2022 were compiled, allowing a 5-year buffer following drug approval in 2017. Reporting odds ratios were calculated for the top 10 ADRs, comparing new diabetic agents to the other approved drugs in their therapeutic class., Results: 127,525 reports were identified for newly approved antidiabetic medications listed as the primary suspect (PS). For sodium-glucose co-transporter-2 (SGLT-2) inhibitors, the odds of blood glucose increased, nausea, and dizziness being reported was greater for empagliflozin. Dapagliflozin was associated with greater reports of weight decreased. Canagliflozin was found to have a disproportionally higher number of reports for diabetic ketoacidosis, toe amputation, acute kidney injury, fungal infections, and osteomyelitis. Assessing glucagon-like peptide-1 (GLP-1) receptor agonists, dulaglutide and semaglutide were associated with greater reports of gastrointestinal adverse drug reactions. Exenatide was disproportionally associated with injection site reactions and pancreatic carcinoma reports., Conclusion: Pharmacovigilance studies utilizing a large publicly available dataset allow an essential opportunity to evaluate the safety profile of antidiabetic drugs utilized in clinical practice. Additional research is needed to evaluate these reported safety concerns for recently approved antidiabetic medications to determine causality., Competing Interests: The authors declare that there is no conflict of interest., (© The Author(s), 2023.)

Sepsis-associated acute kidney injury (SA-AKI) is common in critically ill patients and is strongly associated with adverse outcomes, including an increased risk of chronic kidney disease, cardiovascular events and death. The pathophysiology of SA-AKI remains elusive, although microcirculatory dysfunction, cellular metabolic reprogramming and dysregulated inflammatory responses have been implicated in preclinical studies. SA-AKI is best defined as the occurrence of AKI within 7 days of sepsis onset (diagnosed according to Kidney Disease Improving Global Outcome criteria and Sepsis 3 criteria, respectively). Improving outcomes in SA-AKI is challenging, as patients can present with either clinical or subclinical AKI. Early identification of patients at risk of AKI, or at risk of progressing to severe and/or persistent AKI, is crucial to the timely initiation of adequate supportive measures, including limiting further insults to the kidney. Accordingly, the discovery of biomarkers associated with AKI that can aid in early diagnosis is an area of intensive investigation. Additionally, high-quality evidence on best-practice care of patients with AKI, sepsis and SA-AKI has continued to accrue. Although specific therapeutic options are limited, several clinical trials have evaluated the use of care bundles and extracorporeal techniques as potential therapeutic approaches. Here we provide graded recommendations for managing SA-AKI and highlight priorities for future research., (© 2023. Springer Nature Limited.)

Kratom is a widely used Asian botanical that has gained popularity in the United States due to a perception that it can treat pain, anxiety, and opioid withdrawal symptoms. The American Kratom Association estimates 10-16 million people use kratom. Kratom-associated adverse drug reactions (ADRs) continue to be reported and raise concerns about the safety profile of kratom. However, studies are lacking that describe the overall pattern of kratom-associated adverse events and quantify the association between kratom and adverse events. ADRs reported to the US Food and Drug Administration Adverse Event Reporting System from January 2004 through September 2021 were used to address these knowledge gaps. Descriptive analysis was conducted to analyze kratom-related adverse reactions. Conservative pharmacovigilance signals based on observed-to-expected ratios with shrinkage were estimated by comparing kratom to all other natural products and drugs. Based on 489 deduplicated kratom-related ADR reports, users were young (mean age 35.5 years), and more often male (67.5%) than female patients (23.5%). Cases were predominantly reported since 2018 (94.2%). Fifty-two disproportionate reporting signals in 17 system-organ-class categories were generated. The observed/reported number of kratom-related accidental death reports was 63-fold greater than expected. There were eight strong signals related to addiction or drug withdrawal. An excess proportion of ADR reports were about kratom-related drug complaints, toxicity to various agents, and seizures. Although further research is needed to assess the safety of kratom, clinicians and consumers should be aware that real-world evidence points to potential safety threats., (© 2023 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background: Damage biomarkers are helpful in early identification of patients who are at risk of developing acute kidney injury (AKI). Investigations are ongoing to identify the optimal role of stress/damage biomarkers in clinical practice regarding AKI risk prediction, surveillance, diagnosis, and prognosis., Objective: To determine the impact of utilizing a clinical decision support system (CDSS) to guide stress biomarker testing in intensive care unit (ICU) patients at risk for drug-induced acute kidney injury (D-AKI)., Methods: A protocol was designed utilizing a clinical decision support system (CDSS) alert to identify patients that were ordered 3 or more potentially nephrotoxic medications, suggesting risk for progressing to AKI from nephrotoxic burden. Once alerted to these high-risk patients, the pharmacist determined if action was needed by ordering a stress biomarker test, tissue inhibitor of metalloproteinase-2-insulin-like growth factor-binding protein 7 (TIMP-2•IGFBP7). If the biomarker test result was elevated, the pharmacist provided nephrotoxin stewardship recommendations to the team. Pharmacists recorded the response to the clinical decision support alert, ordering, and interpreting the TIMP-2•IGFBP7, and information regarding clinical interventions. An alert in conjunction with TIMP-2•IGFBP7 as a strategy for AKI risk prediction and stimulant for patient care management was assessed. In addition, barriers and solutions to protocol implementation were evaluated., Results: There were 394 total activities recorded by pharmacists for 345 unique patients. Ninety-three (93/394; 23.6%) actionable alerts resulted in a TIMP-2•IGFBP7 test being ordered. Thirty-one TIMP-2•IGFBP7 results were >0.3 (31/81; 38.3%), suggesting a high-risk of progression to AKI, which prompted 191 pharmacist/team interventions. On average, there were 1.64 interventions per patient in the low-risk patients, 3.43 in high-risk patients, and 3.75 in the highest-risk patients., Conclusion and Relevance: Stress biomarkers can be used in conjunction with CDSS alerts to affect therapeutic decisions in ICU patients at high-risk for D-AKI.

Background: Pharmacokinetic natural product-drug interactions (NPDIs) occur when botanical or other natural products are co-consumed with pharmaceutical drugs. With the growing use of natural products, the risk for potential NPDIs and consequent adverse events has increased. Understanding mechanisms of NPDIs is key to preventing or minimizing adverse events. Although biomedical knowledge graphs (KGs) have been widely used for drug-drug interaction applications, computational investigation of NPDIs is novel. We constructed NP-KG as a first step toward computational discovery of plausible mechanistic explanations for pharmacokinetic NPDIs that can be used to guide scientific research., Methods: We developed a large-scale, heterogeneous KG with biomedical ontologies, linked data, and full texts of the scientific literature. To construct the KG, biomedical ontologies and drug databases were integrated with the Phenotype Knowledge Translator framework. The semantic relation extraction systems, SemRep and Integrated Network and Dynamic Reasoning Assembler, were used to extract semantic predications (subject-relation-object triples) from full texts of the scientific literature related to the exemplar natural products green tea and kratom. A literature-based graph constructed from the predications was integrated into the ontology-grounded KG to create NP-KG. NP-KG was evaluated with case studies of pharmacokinetic green tea- and kratom-drug interactions through KG path searches and meta-path discovery to determine congruent and contradictory information in NP-KG compared to ground truth data. We also conducted an error analysis to identify knowledge gaps and incorrect predications in the KG., Results: The fully integrated NP-KG consisted of 745,512 nodes and 7,249,576 edges. Evaluation of NP-KG resulted in congruent (38.98% for green tea, 50% for kratom), contradictory (15.25% for green tea, 21.43% for kratom), and both congruent and contradictory (15.25% for green tea, 21.43% for kratom) information compared to ground truth data. Potential pharmacokinetic mechanisms for several purported NPDIs, including the green tea-raloxifene, green tea-nadolol, kratom-midazolam, kratom-quetiapine, and kratom-venlafaxine interactions were congruent with the published literature., Conclusion: NP-KG is the first KG to integrate biomedical ontologies with full texts of the scientific literature focused on natural products. We demonstrate the application of NP-KG to identify known pharmacokinetic interactions between natural products and pharmaceutical drugs mediated by drug metabolizing enzymes and transporters. Future work will incorporate context, contradiction analysis, and embedding-based methods to enrich NP-KG. NP-KG is publicly available at https://doi.org/10.5281/zenodo.6814507. The code for relation extraction, KG construction, and hypothesis generation is available at https://github.com/sanyabt/np-kg., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: Traditional methods used to evaluate changes in kidney function to identify acute kidney injury (AKI) have significant limitations. Damage biomarkers can identify patients at risk for AKI prior to changes in kidney function. While clinical trials have shown that biomarker-guided treatment can improve outcomes, whether these biomarkers can influence providers' choice of treatment strategy for risk prediction, surveillance, or diagnostic evaluation in clinical practice is uncertain., Summary: This case series describes 4 patients at an academic medical center whose care was informed by kidney biomarker utilization in conjunction with a clinical decision support system (CDSS). Though each patient's clinical presentation was unique, kidney biomarkers were successfully employed as clinical tools in evaluating the risks and benefits of nephrotoxic medications., Conclusion: This case series demonstrates 4 scenarios in which a kidney injury biomarker used in conjunction with CDSS and consideration of the patients' clinical presentation informed treatment strategies with the intent to prevent AKI., (© American Society of Health-System Pharmacists 2022. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Drug-associated acute kidney injury (D-AKI) accounts for 19-26% of acute kidney injury (AKI) events in hospitalized patients and results in outcomes similar to patients with AKI from other etiologies. Diagnosing D-AKI is complex and various criteria have been used., Summary: To highlight the variability in D-AKI determination, a review was conducted between January 2017 and December 2022 using PubMed. Search terms included adaptations of "drug associated kidney injury" to identify a sampling of literature discussing definitions and criteria for D-AKI evaluation. The search yielded 291 articles that were uploaded to Rayyan, a software tool used to screen and select studies. Retrospective, observational electronic health record (EHR) studies conducted in hospitalized patients were included. The final sample contained 16 studies for data extraction, representing mostly adult populations (n = 13, 81.3%) in noncritical or unspecified inpatient settings (n = 12, 75%). Nine studies (56.3%) utilized the recommended Kidney Disease: Improving Global Outcome guidelines (KDIGO) criteria to define AKI. Baseline creatinine or laboratory criteria for kidney function were provided in 10 studies (62.5%). Eleven studies (68.8%) established a temporal sequence assessment linking nephrotoxin drug exposure to an AKI event, but these criteria were inconsistent among studies using time frames as soon as 3 months prior to AKI., Conclusion: This review highlights the substantial variability in D-AKI criteria in select studies. Minimum expectations about what should be reported and criteria for the elements reported are needed to assure transparency, consistency, and standardization of pharmacovigilance strategies., (© 2023 The Author(s). Published by S. Karger AG, Basel.)