An Integrated Approach for Representing Knowledge on the Potential of Drugs to Cause Acute Kidney Injury.

INTRODUCTION AND OBJECTIVE: The recent rise in acute kidney injury (AKI) incidence, with approximately 30% attributed to potentially preventable adverse drug events (ADEs), poses challenges in evaluating drug-induced AKI due to polypharmacy and other risk factors. This study seeks to consolidate knowledge on the drugs with AKI potential from four distinct sources: (i) bio(medical) peer-reviewed journals; (ii) spontaneous reporting systems (SRS); (iii) drug information databases (DIDs); and (iv) NephroTox website. By harnessing the potential of these underutilised sources, our objective is to bridge gaps and enhance the understanding of drug-induced AKI. METHODS: By searching Medline, studies with lists of drugs with AKI potential established through consensus amongst medical experts were selected. A final list of 63 drugs was generated aggregating the original studies. For these 63 drugs, the AKI reporting odds ratios (RORs) using three SRS databases, the average frequency of ADEs from four different DIDs and the number of published studies identified via NephroTox was reported. RESULTS: Drugs belonging to the antivirals, antibacterials, and non-steroidal anti-inflammatory pharmacological classes exhibit substantial consensus on AKI potential, which was also reflected in strong ROR signals, frequent to very frequent AKI-related ADEs and a high number of published studies reporting adverse kidney events as identified via NephroTox. Renin-angiotensin aldosterone system inhibitors and diuretics also display comparable signal strengths, but this can be attributed to expected haemodynamic changes. More variability is noted for proton-pump inhibitors. CONCLUSIONS: By integrating four disjointed sources of knowledge, we have created a novel, comprehensive resource on drugs with AKI potential, contributing to kidney safety improvement efforts.

Disease-Modifying Medications in Patients with Rheumatoid Arthritis in the USA: Trends from 2016 to 2021.

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.

A deep learning-based dynamic model for predicting acute kidney injury risk severity in postoperative patients.

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.

Assessing adverse drug reaction reports for antidiabetic medications approved by the food and drug administration between 2012 and 2017: a pharmacovigilance study.

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.

Adverse drug reactions reported for antidiabetic medications Introduction: This study investigated the trends in voluntary reporting of adverse drug reactions for recently approved antidiabetic medications. Methods: Data from the FDA Adverse Events Reporting System were evaluated. The top 10 adverse drug reactions were compared between antidiabetic medications in the same therapeutic class. Results: We identified 127,525 adverse drug reaction reports for the newer approved antidiabetic medications. For SGLT-2 inhibitors, empagliflozin was associated with greater reports of blood glucose increase, nausea, and dizziness; weight decreased was reported more often for dapagliflozin; and diabetic ketoacidosis, toe amputation, acute kidney injury, fungal infections, and osteomyelitis were reported more commonly for canagliflozin. Assessing GLP-1 receptor agonists, the odds of gastrointestinal adverse drug reactions being reported was greater for dulaglutide and semaglutide. Exenatide was disproportionally associated with injection site reactions and pancreatic carcinoma reports. Conclusion: Medication safety studies using a large publicly available dataset allows an essential opportunity to evaluate the safety profile of antidiabetic drugs in the real-world setting. Additional research is needed to determine if the reported safety concerns for recently approved antidiabetic medications to determine causality.

Use of tissue inhibitor of metalloproteinase 2 and insulin-like growth factor binding protein 7 [TIMP2]•[IGFBP7] as an AKI risk screening tool to manage patients in the real-world setting.

PURPOSE: To determine the application of various components of the Kidney Disease Improving Global Outcomes (KDIGO) bundle in managing patients at high-risk for AKI progression ([TIMP2]•[IGFBP7] >0.3) in the real-world setting. METHODS: Patients with a [TIMP2]•[IGFBP7] test ordered between 5/23/16-2/28/18 were evaluated. We reviewed the medical record for evidence of implementation of the KDIGO bundle in response to biomarker test results. Evidence including explicit documentation in physicians' note discussing [TIMP2]•[IGFBP7] results and implicit evidence from review of dose adjusted medications, discontinued nephrotoxins and therapeutic drug monitoring. RESULTS: 105 [TIMP2]•[IGFBP7] tests were conducted in 100 patients (54% female; mean age 55.4 ± 16.8; 89% in the ICU). Sixty-one patients had a value of >0.3 and 46 (75.4%) of these patients received at least one management strategy consistent with KDIGO. By contrast, nine patients (23.1%) with [TIMP2]•[IGFBP7] ≤0.3 received one or more components of the KDIGO bundle (p < .001). CONCLUSION: In a real-world setting the use of urinary [TIMP2]•[IGFBP7] as an AKI risk screening tool resulted in differential application of various components of the KDIGO bundle for patient management for those with a positive test result.

Prediction of the Renal Elimination of Drugs With Cystatin C vs Creatinine: A Systematic Review.

Serum cystatin C has been proposed as a kidney biomarker to inform drug dosing. We conducted a systematic review to synthesize available data for the association between serum cystatin C and drug pharmacokinetics, dosing, and clinical outcomes in adults (≥18 years). PubMed, Ovid MEDLINE, Ovid EMBASE, EBSCO CINAHL, and Scopus were systematically searched from 1946 to September 2017 to identify candidate studies. Studies of cystatin C as a predictor for acute kidney injury or for management of contrast-associated acute kidney injury were excluded. Also, studies were excluded if drug concentrations were unavailable and if a reference standard for drug dosing (eg, serum creatinine) was not concurrently reported. The outcomes of interest included drug clearance (L/h), concentrations (mg/L), target level achievement (%), therapeutic failure (%), and drug toxicity (%). We included 28 articles that evaluated 16 different medications in 3455 participants. Vancomycin was the most well-studied drug. Overall, cystatin C-based estimated glomerular filtration rate (eGFRCystatin C) was more predictive of drug levels and drug clearance than eGFRCreatinine. In only one study were target attainment and outcomes compared between 2 drug-dosing regimens, one based on eGFRCreatinine-Cystatin C and one dosed with the Cockcroft-Gault creatinine clearance equation. Compared with eGFRCreatinine, use of eGFRCystatin C to predict elimination of medications via the kidney was as accurate, if not superior, in most studies, but infrequently were data on target attainment or clinical outcomes reported. Drug-specific dosing protocols that use cystatin C to estimate kidney function should be tested for clinical application.

Innovative Use of Novel Biomarkers to Improve the Safety of Renally Eliminated and Nephrotoxic Medications.

Over the last decade, the discovery of novel renal biomarkers and research on their use to improve medication effectiveness and safety has expanded considerably. Pharmacists are uniquely positioned to leverage this new technology for renal assessment to improve medication dosing and monitoring. Serum cystatin C is a relatively new, inexpensive, functional renal biomarker that responds more quickly to changing renal function than creatinine and is not meaningfully affected by age, sex, skeletal muscle mass, dietary intake, or deconditioning. Cystatin C has been proposed as an adjunct or alternative to creatinine for glomerular filtration rate assessment and estimation of drug clearance. Tissue inhibitor of metalloproteinase-2·insulin-like growth factor-binding protein 7 ([TIMP-2]·[IGFBP7]) is a composite of two damage biomarkers released into the urine at a checkpoint in mitosis when renal cells undergo stress or sense a future risk of damage. Concentrations of [TIMP-2]·[IGFBP7] increase before a rise in serum creatinine is evident, thus providing insightful information for evaluation in the context of other patient data to predict the risk for impending kidney injury. This article provides a brief overview of novel renal biomarkers being used as a mechanism to improve medication safety including a discussion of cystatin C, as part of drug-dosing algorithms and specifically for vancomycin dosing, and the use of [TIMP-2]·[IGFBP7] for risk prediction in acute kidney injury and drug-induced kidney disease. Select cases of clinical experience with novel renal biomarkers are outlined, and lessons learned and future applications are described.

Impact of clinical pharmacist services delivered via telemedicine in the outpatient or ambulatory care setting: A systematic review.

BACKGROUND: Utilization of telemedicine allows pharmacists to extend the reach of clinical interventions, connecting them with patients and providers, but the overall impact of these services is under-studied. OBJECTIVE: Identify the impact of clinical pharmacist telemedicine interventions on clinical outcomes, subsequently defined as clinical disease management, patient self-management, and adherence, in outpatient or ambulatory settings. METHODS: A literature search was conducted from database inception through May 2016 in Medline, SCOPUS, and EMBASE. Broad terms "telemedicine", "telehealth", and "telephone" were used in combination with "pharmacist" or "pharmacy" and "telepharmacy". The search and extraction process followed PRISMA guidelines. Results were screened for pharmacist interventions and reviewed to identify studies in outpatient our ambulatory settings. Studies of non-clinical outcomes (i.e. dispensing or product preparation) and with no comparator were excluded. The final studies were categorized by types of outcomes reported: clinical disease management, patient self-management, and adherence. RESULTS: Only 34 studies measured clinical outcomes against a comparator, consistent with the research question. The majority utilized scheduled models of care (n = 29). Telephone was the most common communication method (n = 25). The most utilized interventions were pharmacist-led telephonic clinics (n = 10). Most studies focused on chronic disease management in adults including hypertension, diabetes, anticoagulation, depression, hyperlipidemia, asthma, heart failure, HIV, PTSD, CKD, stroke, COPD and smoking cessation. Twenty-three studies had a positive impact with one reporting negative results. Higher positive impact rate was observed for scheduled (72.4%, 21/29) and continuous (100%, 2/2) models compared to responsive/reactive (25%, 1/4). CONCLUSIONS: Clinical pharmacy telemedicine interventions in the outpatient or ambulatory setting, primarily via phone, have an overall positive impact on outcomes related to clinical disease management, patient self-management, and adherence in the management of chronic diseases. Commonalities among studies with positive impact included utilization of continuous or scheduled models via telephone, with frequent monitoring and interventions. Studies identified did not evaluate benefits of video capability over telephone or cost-effectiveness, both of which are useful directions for future study.

Triple Antithrombotic Therapy With Aspirin, P2Y12 Inhibitor, and Warfarin After Percutaneous Coronary Intervention: An Evaluation of Prasugrel or Ticagrelor Versus Clopidogrel.

BACKGROUND: Triple antithrombotic therapy is used in patients who require systemic anticoagulation and undergo percutaneous coronary intervention (PCI) requiring dual antiplatelet therapy. Bleeding with this combination is significant; however, few studies have described outcomes with the use of newer oral P2Y12 inhibitors in this setting. OBJECTIVES: We aimed to compare outcomes among patients prescribed triple therapy with prasugrel or ticagrelor compared to triple therapy with clopidogrel in patients who underwent PCI and required warfarin. METHODS: We retrospectively evaluated 168 patients who received either prasugrel (n = 32) or ticagrelor (n = 10) and were matched (1:3) to those who received clopidogrel (n = 126) at the time of discharge from the index PCI visit. Matching was performed based on age ±10 years, sex, and indication for PCI. The primary outcome was the incidence of any bleeding during the 12-month follow-up. We also evaluated major adverse cardiovascular and cerebrovascular events (MACCEs). RESULTS: Patient baseline characteristics were similar between groups. There was a significant excess of bleeding in patients who received prasugrel or ticagrelor compared to clopidogrel as part of triple therapy (28.6% vs 12.7%; odds ratio, 3.3; 95% confidence interval, 1.38-8.34). No differences were seen between groups in MACCEs. CONCLUSIONS: The use of prasugrel or ticagrelor as part of triple antithrombotic therapy among patients who underwent PCI and received warfarin was associated with significantly more bleeding compared to patients who received clopidogrel. Therefore, higher potency P2Y12 inhibitors should be used cautiously in these patients.

Association Between Train-of-Four Values and Gas Exchange Indices in Moderate to Severe Acute Respiratory Distress Syndrome.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is associated with a mortality rate of approximately 40%. Neuromuscular blockade is associated with an improvement in oxygenation and a reduction in mortality in ARDS. OBJECTIVE: The goal of this evaluation was to determine if the depth of paralysis, determined by train-of-four (TOF) monitoring, correlates with gas exchange in moderate to severe ARDS. METHODS: This was a retrospective review of moderate to severe ARDS patients who were prescribed >12 hours of continuous infusion cisatracurium between January 1, 2013, and December 31, 2014, with a PaO2:FiO2 ratio <150 and documented TOF and arterial blood gases. Patients were evaluated for inclusion at 12, 24, and 48 hours after initiation of neuromuscular blockade. RESULTS: A total of 378 patients were screened for inclusion, with 107 evaluable patients meeting criteria at baseline. Poor correlation existed between TOF and oxygenation index (OI) at 12 (τ = 0.03), 24 (τ = 0.15) and 48 hours (τ = 0.08). When controlling for proning and baseline OI, the depth of paralysis did not have a significant effect on OI at 12, 24, or 48 hours. CONCLUSIONS: This evaluation demonstrates that the use of TOF monitoring for neuromuscular blockade does not correlate with gas exchange markers in moderate to severe ARDS.

The implementation of a nonpharmacologic protocol to prevent intensive care delirium.

PURPOSE: The purpose was to determine if the implementation of an evidence-based nonpharmacologic protocol reduced the percentage of time patients spent delirious in a medical intensive care unit (MICU) that already uses a sedation and mobility protocol. MATERIALS AND METHODS: This was a prospective, pre-post quality improvement project of MICU patients conducted from September 2013 to April 2014. Evidence-based effective nonpharmacologic interventions with nursing education were bundled into the project protocol: music, opening/closing of blinds, reorientation/cognitive stimulation, and eye/ear care. RESULTS: Patients were evaluated between September 2013 and April 2014, with 230 and 253 patients being included in the each phase. There was a 50.6% reduction (16.1% vs 9.6%, P < .001) in time spent delirious in the MICU. Incidence of delirium developed was decreased (15.7% vs 9.4%, P = .04). The protocol reduced the odds of developing delirium by 57% (odds ratio, 0.43; P = .005) after controlling for age, Acute Physiology and Chronic Health Evaluation II, mechanical ventilation, and dementia. CONCLUSIONS: The implementation of a nonpharmacologic delirium prevention protocol resulted in a significant decrease in the percentage of time spent delirious in the MICU while reducing the risk of delirium development. Additional studies with more rigorous study designs need to be completed to further the research of nonpharmacologic interventions with appropriate sedation and mobility protocols.

An Evaluation of Adverse Drug Reactions Associated With Antipsychotic Use for the Treatment of Delirium in the Intensive Care Unit.

PURPOSE: This investigation evaluated the incidence, severity, and harm of adverse drug reactions (ADRs) associated with antipsychotic use for intensive care unit (ICU) delirium. METHODS: In this prospective, observational study patients were screened for development of delirium with the Intensive Care Delirium Screening Checklist (ICDSC). An ICDSC score of ≥4 was considered delirious. Patients with delirium were screened daily for ADRs. Suspected ADRs were evaluated for drug causality using 3 published, objective assessment tools. Suspected ADRs were considered positive when 2 of 3 instruments had an agreement rating of "possible" or greater. ADR severity was defined as "mild/moderate" or "severe" using the National Cancer Institute's Common Terminology Criteria for Adverse Events scale. A modified National Coordinating Council Medication Error Reporting Index for Categorizing Errors categorized ADRs into "no harm" or "harmful." RESULTS: Of 90 patients with delirium, 56 received antipsychotics. Ten suspected ADRs occurred attributed to antipsychotic use. QTc prolongation was the most observed ADR (50%). Patients with ADRs had higher mean Acute Physiology and Chronic Health Evaluation II (APACHE II) scores (P = .038). Patients who received haloperidol experienced more severe (P = .048) ADRs. CONCLUSIONS: ADRs were observed in 18% of patients having delirium treated with antipsychotics with about half considered severe or harmful. A risk versus benefit assessment is needed before initiating antipsychotic therapy in ICU patients.

The cost of opioid-related adverse drug events.

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

Clinical and economic evaluation of an evidence-based institutional epoetin-utilization management program.

BACKGROUND: Anemia is common in several patient populations, including those with chronic kidney disease, cancer, and HIV/AIDS, and may require treatment with erythropoietin-stimulating agents (ESAs). Given the potential risks of the ESA, epoetin, and the significant costs associated with this agent, a large teaching medical institution developed a the drug-utilization management program using evidence-based guidelines on appropriate use. OBJECTIVE: This study was designed to determine the clinical and financial impact of the drug-utilization management program. METHODS: This retrospective cohort study was conducted at the medical institution that implemented the program using clinical pharmacists. Patients were included if epoetin was administered during their hospital stay (evaluation period, December 1, 2010, to December 31, 2011). The rate of inappropriate epoetin prescribing and the economic impact of guideline implementation were evaluated using comparisons of data from cohorts prescribed epoetin before and after guideline implementation. RESULTS: Data from 796 patients were included in the analyses (pre-implementation, 496; post-implementation, 300). The proportion of patients prescribed epoetin was significantly smaller after guideline implementation (2.4% vs 1.6%; P < 0.001). The reduction in the total number of epoetin units administered was 45%. The significant reduction (25%) in inappropriate prescribing after guideline implementation was primarily attributed to a 17% decrease in epoetin use in nonspecific anemia. The reduction in inappropriate epoetin prescribing translated into a 23.8% reduction in costs (P < 0.001) associated with inappropriate epoetin use. The estimated annual cost-savings of this program was $198,352 ($16,529/mo). CONCLUSION: The implementation of a drug-utilization management program using clinical pharmacists who evaluated epoetin was associated with a decrease in inappropriate epoetin prescribing and with significant cost-savings.

Use of acetylcysteine for non-acetaminophen-induced acute liver failure.

The purpose of this review was to evaluate the effectiveness of acetylcysteine in the treatment of acute liver failure not related to acetaminophen. A search of MEDLINE April 2003 through May 2012 using the Pub Med database was conducted using the keywords acetylcysteine and non-acetaminophen-induced acute liver failure or acetylcysteine and liver failure. All human case reports, case series, and research articles that discussed the use of acetylcysteine for non-acetaminophen induced liver failure were evaluated. A total of 263 articles were identified during this broad search with 11 articles included for review in this article; eight case reports, two retrospective trials, and one prospective, randomized, double-blind multicenter study. In conclusion, the data suggest marginal benefit of IV acetylcysteine in NAI-ALF with coma grades I-II; however, the routine use of acetylcysteine cannot be recommended. It may be considered in non-transplant centers while awaiting referral or when transplantation is not an option. Further studies are necessary to determine optimal dosing, duration, and criteria for patient selection.

Adverse drug reactions in hospital and ambulatory care settings identified using a large administrative database.

BACKGROUND: Previous studies are limited in sample size and number of sites for the detection and characterization of adverse drug reactions (ADRs) in ambulatory care and hospital settings. OBJECTIVE: To determine the prevalence and distribution of suspected ADRs according to demographic characteristics and drug classes for ambulatory care and hospitalized patients. METHODS: A cross-sectional evaluation of administrative data from 2002-2005, containing a maximum of 20 million Medicare and commercially insured patients in a year, was completed. Individuals with one or more claims suggesting an ADR were identified, using International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) criteria referred to as a "suspected ADR." Frequency of ICD-9-CM codes consistent with suspected ADRs for the 4 years was calculated for hospital and ambulatory care settings, based on age ranges, comorbidities, and drug classes. RESULTS: Between 2002 and 2005, the average annual prevalence of suspected ADRs was 0.5%, with a total of 249,633 suspected ADRs during the 4 years. The mean age of hospitalized patients experiencing a suspected ADR was 12 years older than that of ambulatory care patients and 20 years older than that of the general database population. Diseases of the circulatory and endocrine/nutritional/metabolic systems rank among the top 5 comorbid conditions in hospitalized patients who had a suspected ADR. Injury and poisoning was the primary comorbidity in ambulatory patients. High-risk medications frequently associated with suspected ADRs in both settings were antineoplastic and anticoagulant agents. Other drug classes commonly associated with suspected ADRs in hospitalized patients were antihypertensives and diuretics. For the ambulatory care setting, drug classes frequently associated with suspected ADRs were antirheumatic and antiarteriosclerotic agents. CONCLUSIONS: ADR detection, using administrative data, revealed differences in age, comorbidities, and drug classifications between ambulatory care and hospital settings. The results can be used to develop focused prevention strategies and targeted surveillance for individuals most at risk for developing ADRs.

QT prolongation in the intensive care unit: commonly used medications and the impact of drug-drug interactions.

IMPORTANCE OF THE FIELD: Critically ill patients are at an increased risk to develop drug-drug interactions (DDIs). DDIs that increase the risk of QT prolongation, and ultimately torsades de pointes, can result in a medical emergency. Many clinicians are unaware of the risk of certain drug combinations that may precipitate QT prolongation in the intensive care unit (ICU). Additional DDI education and a review of management strategies could assist with prevention of future adverse outcomes. AREAS COVERED IN THIS REVIEW: This review focuses on some commonly used medications in the ICU that may be involved in pharmacokinetic and/or pharmacodynamic DDIs leading to the development of QT prolongation and possibly torsades de pointes. Also, appropriate management strategies are discussed. WHAT THE READER WILL GAIN: The ICU clinician will gain a better understanding of common medications used in the ICU and DDIs that put patients at risk for the development of QT prolongation and torsades de pointes. TAKE HOME MESSAGE: Medications that may cause QT prolongation are common in the ICU and DDIs need to be identified and prevented by the clinician to avoid a potentially life-threatening dysrrhythmia.

Neuroleptic malignant syndrome in traumatic brain injury patients treated with haloperidol.

BACKGROUND: Haloperidol, which is commonly used to treat agitation in critically ill patients, has been associated with the development of neuroleptic malignant syndrome (NMS). The purpose of this manuscript was to review the literature describing NMS and haloperidol use in patients sustaining a traumatic brain injury (TBI) since these patients may be at greater risk for NMS. METHODS: A computerized search of MEDLINE was conducted (1966-May 2008) to identify all publications in which haloperidol was related to NMS in patients with a TBI. The references of these manuscripts were reviewed for additional literature. RESULTS: Nine case reports describe the development of NMS in patients with TBI treated with haloperidol for agitation. Cumulative haloperidol doses before the onset of NMS ranged from 10 mg to at least 210 mg. Most of these patients received high dose (> or =30 mg) haloperidol. Four patients received haloperidol parenterally. On diagnosis, of NMS, haloperidol was discontinued in five cases, and all were given supportive care and pharmacologic treatment. Patients were discharged with improved, but diminished functional capacity. CONCLUSION: Development of NMS in TBI patients treated with haloperidol should be a concern for clinicians since these patients may be at greater risk for this adverse event; especially if the patient is receiving haloperidol at high doses parenterally. Future studies are needed to evaluate the incidence and increased risk of adverse events in patients sustaining a TBI and receiving haloperidol especially since haloperidol is being used more frequently in the critically ill patients.

Coronary vasospasm and atrial fibrillation associated with ondansetron therapy.

OBJECTIVE: To provide further evidence of cardiovascular adverse effects of ondansetron, including new-onset atrial fibrillation, ST segment elevation, and chest pain subsequent to ondansetron administration, and to review cardiovascular adverse events related to several 5-hydroxytryptamine type 3 (5-HT(3)) receptor antagonists. CASE SUMMARY: A 51-year-old male with an uncomplicated past medical history was admitted for an elective inguinal hernia repair and septoplasty. His maintenance medications were discontinued prior to surgery. After a second 4-mg dose of intravenous ondansetron was administered, he developed nausea and diaphoresis. His electrocardiograph revealed new-onset atrial fibrillation and inferolateral ST segment elevation with ST segment alternans. During emergent cardiac catheterization, no obstructive coronary artery disease was evident. The patient's heart rhythm was electrically converted to normal sinus rhythm. During 3 years of follow-up, he has had no return of chest pain or hypotension. DISCUSSION: Although considered a safe class of medications by many clinicians, several of the 5-HT(3) receptor antagonists have been associated with serious cardiovascular effects. Three case reports described cardiac dysrhythmias and 9 documented coronary vasospasm and chest pain, possibly resulting from ondansetron. This is the first reported case of a combination of hypotension, atrial fibrillation, ST segment elevation, and chest pain following ondansetron administration after elective surgery in a healthy adult male with a nonconfounding medication profile. The Naranjo probability scale indicated that ondansetron was the probable cause of these cardiovascular events. CONCLUSIONS: This case report supports the concern regarding cardiovascular adverse effects of ondansetron. Clinicians should be aware of cardiovascular adverse reactions that may be associated with intravenous ondansetron and monitor for electrocardiographic changes as indicated. Further investigation is needed to delineate the actual incidence of cardiovascular effects associated with ondansetron and whether the intravenous rate of administration is a contributing factor.