Renin-Angiotensin System Modulation With Synthetic Angiotensin (1-7) and Angiotensin II Type 1 Receptor-Biased Ligand in Adults With COVID-19: Two Randomized Clinical Trials.

Importance: Preclinical models suggest dysregulation of the renin-angiotensin system (RAS) caused by SARS-CoV-2 infection may increase the relative activity of angiotensin II compared with angiotensin (1-7) and may be an important contributor to COVID-19 pathophysiology. Objective: To evaluate the efficacy and safety of RAS modulation using 2 investigational RAS agents, TXA-127 (synthetic angiotensin [1-7]) and TRV-027 (an angiotensin II type 1 receptor-biased ligand), that are hypothesized to potentiate the action of angiotensin (1-7) and mitigate the action of the angiotensin II. Design, Setting, and Participants: Two randomized clinical trials including adults hospitalized with acute COVID-19 and new-onset hypoxemia were conducted at 35 sites in the US between July 22, 2021, and April 20, 2022; last follow-up visit: July 26, 2022. Interventions: A 0.5-mg/kg intravenous infusion of TXA-127 once daily for 5 days or placebo. A 12-mg/h continuous intravenous infusion of TRV-027 for 5 days or placebo. Main Outcomes and Measures: The primary outcome was oxygen-free days, an ordinal outcome that classifies a patient's status at day 28 based on mortality and duration of supplemental oxygen use; an adjusted odds ratio (OR) greater than 1.0 indicated superiority of the RAS agent vs placebo. A key secondary outcome was 28-day all-cause mortality. Safety outcomes included allergic reaction, new kidney replacement therapy, and hypotension. Results: Both trials met prespecified early stopping criteria for a low probability of efficacy. Of 343 patients in the TXA-127 trial (226 [65.9%] aged 31-64 years, 200 [58.3%] men, 225 [65.6%] White, and 274 [79.9%] not Hispanic), 170 received TXA-127 and 173 received placebo. Of 290 patients in the TRV-027 trial (199 [68.6%] aged 31-64 years, 168 [57.9%] men, 195 [67.2%] White, and 225 [77.6%] not Hispanic), 145 received TRV-027 and 145 received placebo. Compared with placebo, both TXA-127 (unadjusted mean difference, -2.3 [95% CrI, -4.8 to 0.2]; adjusted OR, 0.88 [95% CrI, 0.59 to 1.30]) and TRV-027 (unadjusted mean difference, -2.4 [95% CrI, -5.1 to 0.3]; adjusted OR, 0.74 [95% CrI, 0.48 to 1.13]) resulted in no difference in oxygen-free days. In the TXA-127 trial, 28-day all-cause mortality occurred in 22 of 163 patients (13.5%) in the TXA-127 group vs 22 of 166 patients (13.3%) in the placebo group (adjusted OR, 0.83 [95% CrI, 0.41 to 1.66]). In the TRV-027 trial, 28-day all-cause mortality occurred in 29 of 141 patients (20.6%) in the TRV-027 group vs 18 of 140 patients (12.9%) in the placebo group (adjusted OR, 1.52 [95% CrI, 0.75 to 3.08]). The frequency of the safety outcomes was similar with either TXA-127 or TRV-027 vs placebo. Conclusions and Relevance: In adults with severe COVID-19, RAS modulation (TXA-127 or TRV-027) did not improve oxygen-free days vs placebo. These results do not support the hypotheses that pharmacological interventions that selectively block the angiotensin II type 1 receptor or increase angiotensin (1-7) improve outcomes for patients with severe COVID-19. Trial Registration: ClinicalTrials.gov Identifier: NCT04924660.

Diphenhydramine-Induced Antimuscarinic Delirium Treated with Physostigmine and Transdermal Rivastigmine.

INTRODUCTION: Recurrent physostigmine shortages present a challenge to healthcare providers treating antimuscarinic delirium. Other centrally acting acetylcholinesterase inhibitors such as rivastigmine may represent a therapeutic alternative or adjunct during physostigmine shortage; however, previous reports of use have not documented serum antimuscarinic toxin concentrations, limiting evaluation of effectiveness. Combination therapy with physostigmine and rivastigmine has not been described. In this report, the authors present a case of diphenhydramine-induced antimuscarinic delirium with elevated diphenhydramine serum concentrations treated with physostigmine and transdermal rivastigmine without observed adverse effect. CASE REPORT: A 48-year-old female presented to an emergency department after ingesting 3.75 g (41.2 mg/kg) of diphenhydramine. She had antimuscarinic delirium with a presenting serum diphenhydramine concentration of 1500 ng/mL (therapeutic range, 25-112 ng/mL) and required two doses of physostigmine to avert intubation prior to intensive care unit (ICU) admission. At hospital hour 22, in the ICU, antimuscarinic delirium persisted but no further physostigmine was available due to hospital shortage. Therefore, a 9.5-mg transdermal rivastigmine patch was applied. By hospital hour 24, her delirium had resolved. A serum diphenhydramine concentration at hospital hour 25 was elevated at 760 ng/mL. Transdermal rivastigmine was discontinued at hospital hour 48 without recurrent delirium. Despite persistent normal mental status after rivastigmine discontinuation, the patient had a dry mouth, difficulty urinating, and mydriasis until hospital day 5. She never developed muscarinic toxicity. DISCUSSION: Transdermal rivastigmine may be a useful treatment alternative or adjunct during physostigmine shortage for antimuscarinic delirium and has a long duration of action without aspiration risk. Muscarinic toxicity was not observed.

Addressing gender inequities: Creation of a multi-institutional consortium of women physicians in academic emergency medicine.

Gender inequity is pervasive in medicine, including emergency medicine (EM), and is well documented in workforce representation, leadership, financial compensation, and resource allocation. The reasons for gender inequities in medicine, including academic EM, are multifactorial and include disadvantageous institutional parental, family, and promotion policies; workplace environment and culture; implicit biases; and a paucity of women physician leader role models, mentors, and sponsors. To address some of the challenges of gender inequities and career advancement for women in academic EM, we established an innovative, peer-driven, multi-institutional consortium of women EM faculty employed at four distinct hospitals affiliated with one medical school. The consortium combined financial and faculty resources to execute gender-specific programs not feasible at an individual institution due to limited funding and faculty availability. The programs included leadership skill-building and negotiation seminars for consortium members. The consortium created a collaborative community designed specifically to enrich career development for women in academic EM, with a formal organizational structure to connect faculty from four hospitals under one academic institution. The objective of this report is to describe the creation of this cross-institutional consortium focused on career development, academic productivity, and networking and sharing best practices for work-life integration for academic EM women faculty. This consortium-building model could be used to enhance existing institutional career development structures for women and other physician communities in academic medicine with unique career advancement challenges.

Impact of a Mandatory Prescription Drug Monitoring Program Check on Emergency Department Opioid Prescribing Rates.

BACKGROUND: Prescription drug monitoring programs (PDMPs) exist in 49 states to guide opioid prescribing. In 40 states, clinicians must check the PDMP prior to prescribing an opioid. Data on mandated PDMP checks show mixed results on opioid prescribing. OBJECTIVES: This study sought to examine the impact of the Massachusetts mandatory PDMP check on opioid prescribing for discharges from an urban tertiary emergency department (ED). METHODS: This was a retrospective cohort study of discharges from one ED from 7/1/2010-10/15/2018. The primary outcome was the monthly percentage of patients discharged from the ED with an opioid prescription. The intervention was Massachusetts mandating a PDMP check for all opioid prescriptions. Prescribing was compared pre- and post-mandate. Interrupted time series (ITS) analysis accounted for known declining trends in opioid prescribing. RESULTS: Of 273,512 ED discharges, 35,050 (12.8%) received opioid prescriptions. Mean monthly opioid prescribing decreased post-intervention from 15.1% (SD ± 3.5%) to 5.1% (SD ± 0.9%; p < 0.001). ITS showed equal pre and post-intervention slopes (-0.002, p = 0.819). A small immediate decrease occurred in prescribing around the mandated check: a 3-month level effect decrease of 0.018 (p = 0.039), 6-month level effect 0.019 (p = 0.023), and a 12-month level effect of 0.020 (p = 0.019). The 24-month level effect was not decreased. CONCLUSION: Prior to the mandated PDMP check, ED opioid prescribing was declining. The mandate did not change the rate of decline but was associated with a non-sustained drop in opioid prescribing immediately following enactment.

Opioid-associated amnestic syndrome: Description of the syndrome and validation of a proposed definition.

OBJECTIVE: An opioid-associated amnestic syndrome (OAS) characterized by acute onset memory loss and bilateral hippocampal signal abnormalities on brain imaging in the setting of a history of opioid use, most notably fentanyl, has been reported. To date, however, there is no case definition to assist neurologists and other clinicians in identifying this syndrome. A multi-disciplinary collaboration of physicians, including neurologists, propose diagnostic criteria for OAS using cases that have been published in the medical literature or presented at conferences. METHODS: Cases were classified as confirmed, probable, or possible based on brain imaging findings and history or analytical testing supporting opioid use. Published articles and presentations were identified by discussion with public health authorities and a systematic search of PubMed. Included were articles, abstracts or posters through November 2019 that presented case reports or case series of a new-onset amnestic syndrome associated with bilateral hippocampal injury on imaging and/or prior opioid or other substance use. The percentages of cases that would meet confirmed, probable, or possible criteria were calculated. RESULTS: Twenty-three publications from all sources met criteria for inclusion, accounting for 40 unique cases. Based on the case definition of OAS, 50% (20/40) were confirmed, 25% (10/40) were probable and 25% (10/40) were possible. CONCLUSION: The development of a validated, formal case definition for OAS can assist neurologists and other clinicians in evaluating patients with amnesia and a history of opioid use.

Trends in opioid use disorder and overdose among opioid-naive individuals receiving an opioid prescription in Massachusetts from 2011 to 2014.

AIMS: To examine how the risks of incident opioid use disorder (OUD), non-fatal and fatal overdose have changed over time among opioid-naive individuals receiving an initial opioid prescription. DESIGN: Retrospective, longitudinal study using the Massachusetts Chapter 55 data set, which linked multiple administrative data sets to study the opioid epidemic. We identified the cumulative incidence of OUD, non-fatal and fatal overdose among the opioid-naive initiating opioid treatment in Massachusetts from 2011 to 2014 and estimated rates of these outcomes at 6 months and at 1, 2, 3 and 4 years to 2015. We used Cox regression to examine the association between characteristics of the initial prescription and risk of these outcomes. SETTING: Massachusetts, USA. PARTICIPANTS: Massachusetts residents aged ≥ 11 years in 2011-15 who were opioid-naive (no opioid prescriptions or evidence of OUD in the 6 months prior to the index prescription) (n = 2 154 426). The mean age was 49.1 years, 55.3% were female and 47.3% had commercial insurance. MEASUREMENTS: Opioid prescriptions were identified in the Prescription Monitoring Program (PMP) database, as were the characteristics of the initial prescription database. The outcomes of OUD and non-fatal overdose were identified from claims in the All Payer Claims Database (APCD) and hospital encounters in the acute hospital case mix files. Fatal overdoses were identified using Registry of Vital Records and Statistics (RVRS) death certificates and the Office of the Chief Medical Examiner (OCME) circumstances of death and toxicology reports. FINDINGS: Among opioid-naive individuals receiving an initial opioid prescription, the risk of incident OUD appears to have declined between 2011 and 2014, while rates of overdose were largely unchanged. For example, the 1-year OUD rate was 1.18% in 2011, 1.11% in 2012, 1.26% in 2013 and 0.94% in 2014. Longer therapy duration was associated with higher risk of OUD [hazard ratio (HR) = 2.24, 95% confidence interval (CI) = 2.19-2.29 for duration of 3 or more months], non-fatal (HR = 1.67, 95% CI = 1.53-1.82) and fatal opioid overdose (HR = 2.24, 95% CI = 1.91-2.61). Concurrent benzodiazepine treatment was also associated with higher risk of OUD (HR = 1.14, 95% CI = 1.12-1.17), non-fatal (HR = 1.20, 95% CI = 1.10-1.30) and fatal overdose (HR = 1.86, 95% CI = 1.61-2.16). CONCLUSIONS: Among opioid-naive individuals in Massachusetts receiving an initial opioid prescription, the risk of incident opioid use disorder appears to have declined between 2011 and 2014, while rates of overdose were largely unchanged. Longer therapy duration and concurrent benzodiazepines were associated with higher rates of opioid use disorder and opioid overdose.

Pediatric Poisonings in a Rural Ugandan Emergency Department.

OBJECTIVE: This study aims to describe pediatric poisonings presenting to a rural Ugandan emergency department (ED), identifying demographic factors and causative agents. METHODS: This retrospective study was conducted in the ED of a rural hospital in the Rukungiri District of Uganda. A prospectively collected quality assurance database of ED visits was queried for poisonings in patients under the age of 5 who were admitted to the hospital. Cases were included if the chief complaint or final diagnosis included anything referable to poisoning, ingestion, or intoxication, or if a toxicologic antidote was administered. The database was coded by a blinded investigator, and descriptive statistics were performed. RESULTS: From November 9, 2009, to July 11, 2014, 3428 patients under the age of 5 were admitted to the hospital. A total of 123 cases (3.6%) met the inclusion criteria. Seventy-two patients were male (58.5%). The average age was 2.3 (SD, 0.97) years with 45 children (36.6%) under the age of 2 years. There were 19 cases (15.4%) lost to 3-day follow-up. The top 3 documented exposures responsible for pediatric poisonings were cow tick or organophosphates (36 cases, 29.2%), general poison or drug overdose (26 cases, 21.1%), and paraffin or hydrocarbon (24 cases, 19.5%).Of the admitted patients, 1 died in the ED and 2 died at 72-hour follow-up, for an overall 72-hour mortality of 2.4%. Patients who died were exposed to iron, cow tick, and rat poison. CONCLUSIONS: Pediatric poisoning affects patients in rural sub-Saharan Africa. The mortality rate at one rural Ugandan hospital was greater than 2%.

Gender differences in funding among grant recipients in emergency medicine: A multicenter analysis.

OBJECTIVE: To describe differences in funded grants between male and female faculty in two academic emergency departments. METHODS: This was a retrospective analysis of grant funding at two academic emergency departments from January 2012-September 2018. We queried the grants department databases at each institution and obtained records of all funded grants for emergency medicine (EM) faculty. We extracted the following information for each award: gender of the principal investigator (PI), PI academic rank, grant mechanism (government, institutional, industry, organizational), and percent effort. Differences by gender were compared using Chi-square or Fisher's exact test and Wilcoxon-rank sum. RESULTS: One-hundred and thirty grants were awarded to EM faculty at the two institutions during the study period. Of the funded grants, 35 (27%) of recipients were female. Among grant recipients, females held lower academic ranking than males (p-value < 0.001): Instructor (49% vs 51%), Assistant Professor (36% vs 64%), Associate Professor (9% vs 91%), and Professor (0% vs 100%), respectively. Organizational grants were dispersed equally between funded faculty, but females received a fewer government, industry, and institutional grants (p-value = 0.007). Female grant recipients were awarded a higher median percent of effort compared to males (14% [IQR: 3-51] vs 8% [IQR: 1-15], respectively, p-value = 0.023). CONCLUSION: In this multicenter analysis, gender discrepancies exist among funded grants of EM faculty. Male recipients had higher academic ranking than their female counterparts. Female recipients were less likely to have government, institutional, and industry grants but received a greater percent effort on funding that was awarded.

How Emergency Physicians Approach Refusal of Observation after Naloxone Resuscitation.

BACKGROUND: Patients who are resuscitated with naloxone frequently refuse a period of observation, even though they may be suffering from a variety of medical and psychiatric comorbidities. Emergency physicians (EPs) are then confronted with the challenge of how best to serve patients' interests while respecting autonomy. OBJECTIVES: We sought to characterize how EPs think about this kind of dilemma and the strategies they use to resolve them. METHODS: We conducted qualitative semi-structured interviews with a convenience sample of 59 emergency physicians attending the American College of Emergency Physicians' Scientific Assembly in October 2018. Three case vignettes highlighting different clinical and ethical features served as prompts. Interviews were analyzed using a constant comparative method to identify patterns of responses and derive key themes. RESULTS: Across the vignettes, EPs demonstrated diverse approaches to observation, assessing decision-making capacity and encouraging compliance. Some EPs refused to comply with a patient's wishes even when they had determined a patient demonstrated capacity. Conversely, a few EPs were willing to allow patients to leave the emergency department (ED) without assessing capacity, or despite determining that the patient lacked capacity. Common reasons for complying with patients' demands were concerns about the patients' rights and concerns about the safety of staff. Most physicians interviewed reported no institutional guidelines or education on the topic, and many physicians expressed an interest in providing medication for addiction treatment in the ED. CONCLUSIONS: EPs approach this clinical and ethical dilemma in widely divergent ways. Consensus about strategies for navigating patients' wishes relative to clinical concerns are needed to help EPs manage these challenging cases.

Reduction of opioid prescribing through the sharing of individual physician opioid prescribing practices.

BACKGROUND: Drug overdoses are the most common cause of accidental death in the United States, with the majority being attributed to opioids. High per capita opioid prescribing is correlated with higher rates of opioid abuse and death. We aimed to determine the impact of sharing individual prescribing data on the rates of opioid prescriptions written for patients discharged from the emergency department (ED). METHODS: This was a pre-post intervention at a single community ED. We compared opioid prescriptions written on patient discharge before and after an intervention consisting of sharing individual and comparison prescribing data. Clinicians at or over one standard deviation above the mean were notified via standard template electronic communication. RESULTS: For each period, we reported the median number of monthly prescriptions written by each clinician, accounting for the total number of patient discharges. The pre-intervention median was 12.5 prescriptions per 100 patient discharges (IQR 10-19) compared to 9 (IQR 6-11) in the post-intervention period (p < 0.001). This represents a 28% reduction in the overall rate of opioid prescriptions written per patient discharged. Using interrupted time series analysis for monthly rates, this was associated with a reduction in opioid prescriptions, showing a decrease of almost 9 prescriptions for every 100 discharges over the 6 months of the study (p = 0.032). CONCLUSION: Our study demonstrates the sharing of individual opioid prescribing data was associated with a reduction in opioid prescribing at a single institution.

Low-energy Bluetooth for detecting real-world penetrance of bystander naloxone kits: a pilot study.

Opioid overdose is a growing public health emergency in the United States. The antidote naloxone must be administered rapidly after opioid overdose to prevent death. Bystander or "take-home" naloxone programs distribute naloxone to opioid users and other community members to increase naloxone availability at the time of overdose. However, data describing the natural history of take-home naloxone in the hands of at-risk individuals is lacking. To understand patterns of naloxone uptake in at-risk users, we developed a smart naloxone kit that uses low-energy Bluetooth (BLE) to unobtrusively detect the transit of naloxone through a hospital campus. In this paper, we describe development of the smart naloxone kit and results from the first 10 participants in our pilot study.

Drugs and Medical Devices: Adverse Events and the Impact on Women's Health.

A large number of medications and medical devices removed from the market by the US Food and Drug Administration over the past 4 decades specifically posed greater health risks to women. This article reviews the historical background of sex and gender in clinical research policy and describes several approved drugs and devices targeted for use in women that have caused major morbidity and mortality. The intended population for the medications and devices, population affected, approval process, and the basic and legal actions taken against the medication/drug company are also discussed. It is recognized that women are still at risk for harm from unsafe medications and devices, and continued improvements in legislation that promotes inclusion of sex and gender into the design and analysis of research will improve safety for both men and women.

Variation in opioid prescribing patterns between ED providers.

Abuse of opioid prescription drugs has become an epidemic across the developed world. Despite the fact that emergency physicians overall account for a small proportion of total opioids prescribed, the number of prescriptions has risen dramatically in the past decade and, to some degree, contributes to the available supply of opioids in the community, some of which are diverted for non-medical use. Since successfully reducing opioid prescribing on the individual level first requires knowledge of current prescribing patterns, we sought to determine to what extent variation exists in opioid prescribing patterns at our institution. This was a single-institution observational study at a community hospital with an annual ED volume of 47,000 visits. We determined the number of prescriptions written by each provider, both total number and accounting for the number of patients seen. Our primary outcome measure was the level of variation at the physician level for number of prescriptions written per patient. We also identified the mean number of pills written per prescription. We analyzed data from November 13, 2014 through July 31, 2015 for 21 full-time providers. There were a total of 2211 prescriptions for opioids written over this time period for a total of 17,382 patients seen. On a per-patient basis, the rate of opioid prescriptions written per patient during this period was 127 per 1000 visits (95 % CI 122-132). There was a variation on the individual provider level, with rates ranging from 33 per to 332 per 1000 visits. There was also substantial variation by provider in the number of pills written per prescription with coefficient of variation (standard deviation divided by mean) averaged over different opioids ranging from 16 to 40 %. There was significant variation in opioid prescribing patterns at the individual physician level, even when accounting for the number of patients seen.