Geriatric Emergency Medication Safety Recommendations (GEMS-Rx): Modified Delphi Development of a High-Risk Prescription List for Older Emergency Department Patients.

STUDY OBJECTIVE: Half of emergency department (ED) patients aged 65 years and older are discharged with new prescriptions. Potentially inappropriate prescriptions contribute to adverse drug events. Our objective was to develop an evidence- and consensus-based list of high-risk prescriptions to avoid among older ED patients. METHODS: We performed a modified, 3-round Delphi process that included 10 ED physician experts in geriatrics or quality measurement and 1 pharmacist. Consensus members reviewed all 35 medication categories from the 2019 American Geriatrics Society Beers Criteria and ranked each on a 5-point Likert scale (5=highest) for overall priority for avoidance (Round 1), risk of short-term adverse events and avoidability (Round 2), and reasonable medical indications for high-risk medication use (Round 3). RESULTS: For each round, questionnaire response rates were 91%, 82%, and 64%, respectively. After Round 1, benzodiazepines (mean, 4.60 [SD, 0.70]), skeletal muscle relaxants (4.60 [0.70]), barbiturates (4.30 [1.06]), first-generation antipsychotics (4.20 [0.63]) and first-generation antihistamines (3.70 [1.49]) were prioritized for avoidance. In Rounds 2 and 3, hypnotic "Z" drugs (4.29 [1.11]), metoclopramide (3.89 [0.93]), and sulfonylureas (4.14 [1.07]) were prioritized for avoidability, despite lower concern for short-term adverse events. All 8 medication classes were included in the final list. Reasonable indications for prescribing high-risk medications included seizure disorders, benzodiazepine/ethanol withdrawal, end of life, severe generalized anxiety, allergic reactions, gastroparesis, and prescription refill. CONCLUSION: We present the first expert consensus-based list of high-risk prescriptions for older ED patients (GEMS-Rx) to improve safety among older ED patients.

Evaluating Clinical Sequelae of the Carbapenem-Valproate Interaction: A Retrospective Analysis.

Background: Previous studies identified a rapid decrease in valproate serum concentrations when coadministered with a carbapenem; however, the specific consequences and subsequent therapy adjustments are not well described. We aimed to investigate the clinical and therapeutic implications of the carbapenem-valproate drug-drug interaction. Methods: This retrospective analysis included data from 2 large academic medical centers during January 2017 to June 2022. The primary outcome was incidence of seizures or behavioral events stratified by valproate indication. All adult patient encounters with concomitant administration of any carbapenem antimicrobial and valproate were included. Patients without prolonged exposure to valproate prior to hospitalization, without valproate levels pre- and post-carbapenem administration, with an admitting diagnosis of seizure, with exposure to other agents that decrease valproate concentrations, or who had a seizure during the hospitalization prior to carbapenem exposure were excluded. Results: Two hundred fifty-eight episodes of concomitant use among 78 unique adult patients were included. Valproate was used for seizure control in 41 patients (52.6%) and for mood-related disorders in 37 (47.4%). In those prescribed valproate for its antiepileptic properties, seizures occurred following carbapenem administration in 46.3% of encounters. In those taking valproate for mood-related disorders, 50.8% met the primary endpoint of behavioral disturbance. Conclusions: Our study demonstrates significant clinical implications of the carbapenem-valproate interaction. Clinicians should be aware of this interaction and consider alternative antimicrobial and/or antiepileptic agents whenever possible. Adding or increasing doses of antiepileptic agents and/or consultation with a neurologist prior to concomitant use should be considered when this combination cannot be avoided.

Evaluation of Medication Exposure on Exacerbation of Disease in Patients With Myasthenia Gravis.

Background and Purpose: In patients with myasthenia gravis (MG), worsening of symptoms poses a risk of respiratory failure which can be precipitated by medication use. Although purported, the risks associated with administration of certain medications are not fully elucidated. Thus, clinical decision support involving a best practice alert was executed to caution providers of drug-disease interactions when ordering a potentially harmful medication. We performed an analysis of the alert overrides with subsequent medication exposure to determine the incidence of MG exacerbations. Methods: This retrospective chart-review evaluated adult patients with MG at 2 large academic medical centers via electronic health records between November-2019 and November-2021 who received a medication following override of the clinical decision support tool. The primary outcome was proportion of patient encounters complicated by myasthenic exacerbations after potentially harmful medication administration. Secondary outcomes included changes in motor strength, length of stay, discharge disposition, unplanned level-of-care escalations, and changes to immunosuppressant therapy following medication administration. Results: A total of 70 orders were assessed in 38 patients across 55 encounters. Medications administered during these encounters included macrolides, fluoroquinolones, ß-blockers, calcium channel blockers, and magnesium sulfate. Exacerbation of disease occurred in 7 patient encounters (12.7%) and occurred after intravenous magnesium or intravenous labetalol. In 5/7 events, at least 1 other risk factor associated with a myasthenic exacerbation was present. Conclusions: Of the medications reported to potentially worsen MG, intravenous labetalol and intravenous magnesium were the 2 agents associated with myasthenic exacerbations with a higher incidence in patients harboring additional risk factors.

Adverse Drug Event Prevention and Detection in Older Emergency Department Patients.

Older adults are given therapies to enhance the quality and longevity of life, but with the benefits of medication therapy also comes the potential for adverse drug events (ADEs). Avoiding ADEs has become a national health priority with substantial impact on health outcomes and health care costs. The presence of multimorbidity, changes in physiologic function, and polypharmacy make older adults more vulnerable to medication-related ADEs. Use of interactive support tools in the form of geriatric-friendly medication order sets and geriatric consultations along with pharmacist-led medication review and optimization are imperative to decrease the occurrence of ADEs and unnecessary prescribing cascades.

Safety and Tolerability of 23.4% Hypertonic Saline Administered Over 2 to 5 Minutes for the Treatment of Cerebral Herniation and Intracranial Pressure Elevation.

BACKGROUND: Hyperosmolar therapy is the cornerstone of medical management of sustained elevated intracranial pressure from cerebral edema. Acute intracranial hypertension and herniation is a medical emergency that requires rapid treatment and stabilization to prevent secondary brain injury or death. Intravenous hypertonic sodium chloride (NaCl) 23.4% is an effective treatment modality commonly used in this setting. Because of its high osmolarity, use has historically been limited primarily to central venous line administration as an intermittent infusion due to concerns about thrombophlebitis, injection site pain, and tissue necrosis or injury with extravasation. The objective of this analysis was to prospectively evaluate the safety of administration of 23.4% NaCl as a rapid intravenous push over 2-5 min. METHODS: A prospective analysis of patients admitted between April 2021 and December 2021 who received 23.4% NaCl intravenous push over 2-5 min in a central or peripheral line was performed. Safety end points included incidence of new onset hypotension [defined as systolic blood pressure (SBP) < 90 mm Hg or SBP decrease of at least 20 mm Hg], bradycardia (defined as heart rate < 50 beats per minute), and infusion site reactions documented within 1 h of administration. For secondary safety outcomes, highest and lowest SBP and lowest heart rates documented within 1 h before 23.4% NaCl administration were compared with values collected within 1 h post administration and evaluated by mixed-design analysis of variance test with adjustment for peripheral versus central line administration. RESULTS: We identified 32 patients who received 79 administrations of 23.4% NaCl through a central line or peripheral line during the study period. An SBP decrease of at least 20 mm Hg was observed in 13% of patients, an SBP < 90 mm Hg occurred in 16% of patients, and bradycardia occurred in 3% of patients who received 23.4% NaCl. Injection site pain was reported by one patient without documented thrombophlebitis, cellulitis, or tissue damage. Pain was not reported during two subsequent administrations in the same patient. There was no documented occurrence of soft tissue injury or necrosis in any patient. Compared with baseline vital signs before 23.4% NaCl administration, no difference in vital signs post administration was observed. CONCLUSIONS: Central and peripheral administration of 23.4% NaCl over 2-5 min was well tolerated, and incidence of hypotension, bradycardia, or infusion site-related adverse events was rare.

Cardiovascular Pharmacology.

Pharmacologic therapy is an integral component in the management of most cardiovascular emergencies. This article reviews the pharmacotherapy involved in the treatment of acute coronary syndromes, acute heart failure, and various arrhythmias. The focus will be to provide practical pearls that can be applied at the bedside in the Emergency Department.

High risk and low prevalence diseases: Acute chest syndrome in sickle cell disease.

INTRODUCTION: Acute chest syndrome (ACS) in sickle cell disease (SCD) is a serious condition that carries with it a high rate of morbidity and mortality. OBJECTIVE: This review highlights the pearls and pitfalls of ACS in SCD, including diagnosis and management in the emergency department (ED) based on current evidence. DISCUSSION: ACS is defined by respiratory symptoms and/or fever and a new radiodensity on chest imaging in a patient with SCD. There are a variety of inciting causes, including infectious and non-infectious etiologies. Although ACS is more common in those with homozygous SCD, clinicians should consider ACS in all SCD patients, as ACS is a leading cause of death in SCD. Patients typically present with or develop respiratory symptoms including fever, cough, chest pain, and shortness of breath, which can progress to respiratory failure requiring mechanical ventilation in 20% of adult patients. However, the initial presentation can vary. While the first line imaging modality is classically chest radiograph, lung ultrasound has demonstrated promise. Further imaging to include computed tomography may be necessary. Management focuses on analgesia, oxygen supplementation, incentive spirometry, bronchodilators, rehydration, antibiotics, consideration for transfusion, and specialist consultation. Empiric antibiotics that cover atypical pathogens are necessary along with measures to increase oxygen-carrying capacity in those with hypoxemia such as simple transfusion or exchange transfusion. CONCLUSIONS: An understanding of ACS can assist emergency clinicians in diagnosing and managing this potentially deadly disease.

Continuation of outpatient buprenorphine therapy after dispensing Buprenorphine-Naloxone from the emergency department.

BACKGROUND: Patients with opioid use disorder (OUD) are frequently seen in the ED for opioid-related reasons, which creates an opportunity for ED providers to discuss medications for OUD with their patients. Buprenorphine is a partial mu-opioid agonist that is FDA approved to treat OUD and may be initiated in the ED. Traditionally, buprenorphine therapy was initiated under healthcare provider observation; however, other strategies such as at-home induction have also emerged. METHODS: This was a retrospective descriptive analysis of patients aged 18 years or older who received a take-home supply of buprenorphine-naloxone from an urban, academic ED between March 2018 and March 2020. The primary outcome was the proportion of patients who filled a prescription for buprenorphine at three months after index ED visit. The proportion of patients that filled a prescription for buprenorphine at six months was also evaluated. The primary safety endpoint was the proportion of patients with return ED visit within six months related to opioid overdose. RESULTS: There were 242 patient records reviewed with 155 patients included in final analysis. Seventy (45.2%) patients filled buprenorphine prescriptions at three months, with 64 (41.3%) who filled buprenorphine prescriptions at six months. Seventeen (11%) patients had a return ED visit related to opioid overdose within six months. CONCLUSION: Dispensing buprenorphine take-home kits from the ED resulted in continuation of outpatient buprenorphine in almost 50% of patients. Further studies are warranted to define the role of ED-dispensed buprenorphine.

Heart rate outcomes with concomitant parenteral calcium channel blockers and beta blockers in rapid atrial fibrillation or flutter.

BACKGROUND: Patients who present with atrial fibrillation (AF) or flutter with rapid ventricular response (RVR) and hemodynamic stability may be managed with either an intravenous (IV) nondihydropyridine calcium channel blocker (CCB) or a beta-blocker (BB). Patients without improved heart rates may need to switch to, or add, a second AV nodal blocker. OBJECTIVE: To evaluate the incidence of rate control achievement and bradycardia in patients in AF or atrial flutter with RVR who receive both an intravenous CCB and a BB. METHODS: A retrospective chart review of patients who received concomitant intravenous CCB or BB for the treatment of rapid AF or atrial flutter from April 2016 through July 2018 in the emergency department. Patients were excluded if the second agent was ordered but not administered, or if they received IV amiodarone or digoxin. RESULTS: A total of 136 patients were included in the analysis, and of those, 46% (n = 62) of patients achieved a heart rate <110 bpm without bradycardia, and 3.7% (n = 5) developed bradycardia. Age, initial heart rate, time between CCB and BB administration, addition of an oral CCB or BB administration, or administration of IV magnesium did not impact target heart rate achievement. CONCLUSION: Adding a second nodal blocker in patients who did not achieve rate control with the first agent resulted in heart rate control 46% of the time. The development of symptomatic bradycardia was uncommon.

Assessment and Optimization of the Empiric Treatment of Urinary Tract Infections in an Academic Emergency Department Observation Unit.

BACKGROUND: Poor adherence to evidence-based guidelines and overuse of broad-spectrum antibiotics has been noted in the emergency department (ED). There is limited evidence on guideline-congruent empiric therapy for urinary tract infections (UTIs) and uropathogen susceptibilities in the ED observation unit (EDOU). OBJECTIVE: The primary objective was to evaluate the prescribing patterns for the empiric treatment of UTI in the EDOU. Secondary objectives were to analyze uropathogen susceptibilities in the EDOU and implement an algorithm for the empiric treatment of UTI. METHODS: This study retrospectively reviewed adult patients who received empiric UTI treatment in the EDOU from January 1, 2018 to April 1, 2018. Eligible patients were categorized as having either uncomplicated or complicated cystitis, or pyelonephritis based on their clinical diagnosis. Antimicrobial therapy was evaluated in accordance with national practice guidelines, institutional guidelines, and local antimicrobial susceptibility patterns. RESULTS: Patients with uncomplicated or complicated cystitis (n = 115) were provided guideline-congruent empiric treatment in 87% of cases. Patients with pyelonephritis (n = 35) were provided guideline-congruent empiric treatment in 57% of cases. Susceptibility patterns of uropathogens isolated from this patient sample differed slightly from the institutional antibiogram, notably depicting a lower Escherichia coli susceptibility rate. Fluoroquinolones were prescribed for a longer than recommended duration in 18 patients (60%). CONCLUSIONS: The majority of patients in this study were provided guideline-congruent empiric therapy. Nevertheless, there are opportunities to optimize empiric UTI treatment and improve antibiotic stewardship in the EDOU.

A comprehensive evaluation of apixaban in the treatment of venous thromboembolism.

Introduction: The emergence of the direct oral anticoagulants (DOACs) offers patients more convenient and accessible alternatives to warfarin or parenteral agents for the treatment of venous thromboembolism (VTE). Apixaban (Eliquis®) is an oral, direct factor Xa inhibitor that is approved for the acute treatment of deep-vein thrombosis (DVT) and pulmonary embolism (PE) as well as for the reduction in the risk of recurrent DVT and PE following initial therapy.Areas covered: This article reviews results from preclinical and healthy volunteer studies, large phase III trials evaluating the safety and efficacy of apixaban, as well as key studies that led to apixaban's current licensing. This review also will provide an overview of special populations where future areas of research are needed.Expert commentary: Apixaban offers several advantages over historical therapy for the treatment and secondary prevention of VTE. However, there are some populations in which the use of apixaban has not been extensively studied such as patients >75 years old, or those with cancer, low or high body weight, or poor renal function. Likewise, there is a dearth of data on pediatric patients and patients with a history of heparin-induced thrombocytopenia or identified forms of thrombophilia. Additional comparator studies on anticoagulation reversal involving andexanet alfa are also necessary to further assess its hemostatic efficacy and prothrombotic risk.

Medications for management of opioid use disorder.

PURPOSE: The use of buprenorphine, methadone, and long-acting naltrexone for treatment of opioid use disorder (OUD) is discussed, including a review of current literature detailing treatment approaches and action steps to optimize treatment in acute care and office-based settings. SUMMARY: The U.S. epidemic of opioid-related deaths has been driven by misuse of prescription opioids and, increasingly, illicit drugs such as heroin, fentanyl, and fentanyl analogs, necessitating a refocusing of treatment efforts on expanding access to life-saving, evidence-based OUD pharmacotherapy. Inpatient treatment of opioid withdrawal includes acute symptom control through a combination of nonopioid medications and long-term pharmacotherapy to lessen opioid craving and facilitate stabilization and recovery. Methadone and buprenorphine reduce opioid craving, increase treatment retention, reduce illicit opioid use, and increase overall survival. Buprenorphine has logistical advantages over methadone, such as greater flexibility of treatment setting and less risk of adverse effects. Studies have shown the efficacy of long-acting injectable naltrexone to be comparable to that of buprenorphine if patients are detoxified prior to initiation of therapy; however, patients with active OUD are often not able to complete the week-long period of opioid abstinence needed prior to initiation of naltrexone injections. Although buprenorphine is preferred by many patients and can be prescribed in office-based settings, there remains a paucity of physicians certified to prescribe it. CONCLUSION: Buprenorphine has become the medication of choice for many patients with OUD, but its use is limited by the low number of physicians certified to prescribe the agent. Other agents studied for treatment of OUD include methadone and naltrexone.

Managing Subdural Bleeding Associated With Rivaroxaban: A Series of 3 Cases.

OBJECTIVE: To report 3 cases of subdural bleeding associated with rivaroxaban managed by 3-factor prothrombin complex concentrate (PCC3). CASE SUMMARIES: Case 1 presented with a 1-cm thick subdural hematoma (SDH) 12 hours after her last dose of rivaroxaban. Case 2 presented with a right 1-cm acute right SDH with 2 to 3 mm of midline shift 24 hours after his last dose of rivaroxaban. Case 3 presented with a 1.8-cm thick right cerebral convexity hematoma 12 hours after her last dose of rivaroxaban. All patients received 23 to 35 units/kg PCC3 with 1 to 3 units of fresh frozen plasm (FFP) and demonstrated no progression in lesions measured by repeat computed tomography (CT). Two patients were discharged to rehabilitation facilities and 1 patient ultimately died due to the location of the lesion. DISCUSSION: Rivaroxaban has no specific antidote. Current bleeding management strategies are based on expert opinion. The risks and benefits for differing strategies are unclear, and no clinical experience has been reported to date. These cases begin to illuminate differences among choices for managing bleeding associated with Xa inhibitors. CONCLUSION: In this case series, 25 to 35 units/kilogram PCC3 and FFP 1 to 3 units ceased rivaroxaban-associated bleeding without thrombogenic complications.

Metal ions, not metal-catalyzed oxidative stress, cause clay leachate antibacterial activity.

Aqueous leachates prepared from natural antibacterial clays, arbitrarily designated CB-L, release metal ions into suspension, have a low pH (3.4-5), generate reactive oxygen species (ROS) and H2O2, and have a high oxidation-reduction potential. To isolate the role of pH in the antibacterial activity of CB clay mixtures, we exposed three different strains of Escherichia coli O157:H7 to 10% clay suspensions. The clay suspension completely killed acid-sensitive and acid-tolerant E. coli O157:H7 strains, whereas incubation in a low-pH buffer resulted in a minimal decrease in viability, demonstrating that low pH alone does not mediate antibacterial activity. The prevailing hypothesis is that metal ions participate in redox cycling and produce ROS, leading to oxidative damage to macromolecules and resulting in cellular death. However, E. coli cells showed no increase in DNA or protein oxidative lesions and a slight increase in lipid peroxidation following exposure to the antibacterial leachate. Further, supplementation with numerous ROS scavengers eliminated lipid peroxidation, but did not rescue the cells from CB-L-mediated killing. In contrast, supplementing CB-L with EDTA, a broad-spectrum metal chelator, reduced killing. Finally, CB-L was equally lethal to cells in an anoxic environment as compared to the aerobic environment. Thus, ROS were not required for lethal activity and did not contribute to toxicity of CB-L. We conclude that clay-mediated killing was not due to oxidative damage, but rather, was due to toxicity associated directly with released metal ions.

pH-Dependent metal ion toxicity influences the antibacterial activity of two natural mineral mixtures.

BACKGROUND: Recent studies have demonstrated that several mineral products sold for medicinal purposes demonstrate antimicrobial activity, but little is known about the physicochemical properties involved in antibacterial activity. METHODOLOGY/PRINCIPAL FINDINGS: Using in vitro mineral suspension testing, we have identified two natural mineral mixtures, arbitrarily designated BY07 and CB07, with antibacterial activity against a broad-spectrum of bacterial pathogens. Mineral-derived aqueous leachates also exhibited antibacterial activity, revealing that chemical, not physical, mineral characteristics were responsible for the observed activity. The chemical properties essential for bactericidal activity against Escherichia coli were probed by testing antibacterial activity in the presence of metal chelators, the hydroxyl radical scavenger, thiourea, and varying pH levels. Chelation of the BY07 minerals with EDTA or desferrioxamine eliminated or reduced BY07 toxicity, respectively, suggesting a role of an acid-soluble metal species, particularly Fe(3+) or other sequestered metal cations, in mineral toxicity. This conclusion was supported by NMR relaxation data, which indicated that BY07 and CB07 leachates contained higher concentrations of chemically accessible metal ions than leachates from non-bactericidal mineral samples. CONCLUSIONS/SIGNIFICANCE: We conclude that the acidic environment of the hydrated minerals significantly contributes to antibacterial activity by increasing the availability and toxicity of metal ions. These findings provide impetus for further investigation of the physiological effects of mineral products and their applications in complementary antibacterial therapies.

Cell wall composition and decreased autolytic activity and lysostaphin susceptibility of glycopeptide-intermediate Staphylococcus aureus.

The cell wall composition and autolytic properties of passage-selected glycopeptide-intermediate Staphylococcus aureus (GISA) isolates and their parent strains were studied in order to investigate the mechanism of decreased vancomycin susceptibility. GISA had relatively modest changes in peptidoglycan composition involving peptidoglycan interpeptide bridges and somewhat decreased cross-linking compared to that of parent strains. The cell wall phosphorus content of GISA strains was lower than that of susceptible parent strains, indicating somewhat lower wall teichoic acid levels in the GISA strains. Similar to whole cells, isolated crude cell walls retaining autolytic activity of GISA had drastically reduced autolytic activity compared to that of parent strains, and this arose early in the development of the GISA phenotype. This was due to an alteration in the autolytic enzymes of GISA as revealed by normal susceptibility of GISA-purified cell walls to parental strain autolysin extract and lower activity and altered peptidoglycan hydrolase activity profiles in GISA autolysin extracts compared to those of parent strains. Northern blot analysis indicated that expression of atl, the major autolysin gene, was significantly downregulated in a GISA strain compared to that of its parent strain. In contrast to whole cells, which showed decreased lysostaphin susceptibility, purified cell walls of GISA showed increased susceptibility to lysostaphin. We suggest that in our GISA strains, decreased autolytic activity is involved in the tolerance of vancomycin and the activities of endogenous autolysins are important in conferring sensitivity to lysostaphin on whole cells.