Empagliflozin in Heart Failure: Regional Nephron Sodium Handling Effects.

SIGNIFICANCE STATEMENT: The effect of sodium-glucose cotransporter-2 inhibitors (SGLT2i) on regional tubular sodium handling is poorly understood in humans. In this study, empagliflozin substantially decreased lithium reabsorption in the proximal tubule (PT) (a marker of proximal tubular sodium reabsorption), a magnitude out of proportion to that expected with only inhibition of sodium-glucose cotransporter-2. This finding was not driven by an "osmotic diuretic" effect; however, several parameters changed in a manner consistent with inhibition of the sodium-hydrogen exchanger 3. The large changes in proximal tubular handling were acutely buffered by increased reabsorption in both the loop of Henle and the distal nephron, resulting in the observed modest acute natriuresis with these agents. After 14 days of empagliflozin, natriuresis waned due to increased reabsorption in the PT and/or loop of Henle. These findings confirm in humans that SGLT2i have complex and important effects on renal tubular solute handling. BACKGROUND: The effect of SGLT2i on regional tubular sodium handling is poorly understood in humans but may be important for the cardiorenal benefits. METHODS: This study used a previously reported randomized, placebo-controlled crossover study of empagliflozin 10 mg daily in patients with diabetes and heart failure. Sodium handling in the PT, loop of Henle (loop), and distal nephron was assessed at baseline and day 14 using fractional excretion of lithium (FELi), capturing PT/loop sodium reabsorption. Assessments were made with and without antagonism of sodium reabsorption through the loop using bumetanide. RESULTS: Empagliflozin resulted in a large decrease in sodium reabsorption in the PT (increase in FELi=7.5%±10.6%, P = 0.001), with several observations suggesting inhibition of PT sodium hydrogen exchanger 3. In the absence of renal compensation, this would be expected to result in approximately 40 g of sodium excretion/24 hours with normal kidney function. However, rapid tubular compensation occurred with increased sodium reabsorption both in the loop ( P < 0.001) and distal nephron ( P < 0.001). Inhibition of sodium-glucose cotransporter-2 did not attenuate over 14 days of empagliflozin ( P = 0.14). However, there were significant reductions in FELi ( P = 0.009), fractional excretion of sodium ( P = 0.004), and absolute fractional distal sodium reabsorption ( P = 0.036), indicating that chronic adaptation to SGLT2i results primarily from increased reabsorption in the loop and/or PT. CONCLUSIONS: Empagliflozin caused substantial redistribution of intrarenal sodium delivery and reabsorption, providing mechanistic substrate to explain some of the benefits of this class. Importantly, the large increase in sodium exit from the PT was balanced by distal compensation, consistent with SGLT2i excellent safety profile. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: ClinicalTrials.gov ( NCT03027960 ).

Clinical and utilization outcomes with short stay units vs hospital admission for lower risk decompensated heart failure: a systematic review and meta-analysis.

With over 1 million primary heart failure (HF) hospitalizations annually, nearly 80% of patients who present to the emergency department with decompensated HF (DHF) are hospitalized. Short stay units (SSU) present an alternative to hospitalization, yet the effectiveness of the SSU strategy of care is not well known. This study is to determine the effectiveness of a SSU strategy compared with hospitalization in lower-risk patients with DHF. Our primary outcome was a composite of 30-day mortality and re-hospitalization. Key secondary outcomes included 90-day mortality and re-hospitalization, costs, and 30-day days-alive-and-out-of-hospital (DAOOH). This is a systematic review and meta-analysis, following PRISMA guidelines. MEDLINE, EMBASE, CENTRAL, CINAHL, SCOPUS, and Web of Science were searched from inception through February 2024. Either randomized trials or comparative observational studies were included if they compared outcomes between low-risk ED DHF patients admitted to an SSU (defined as an observation unit with expected stay ≤ 48 h) vs. admitted to the hospital. Two authors independently screened all titles and abstracts and then identified full texts for inclusion. Data extraction and risk of bias assessments were performed by two authors in parallel. The primary outcome was a composite of death or readmission within 30 days, reported as relative risk (RR), where a RR < 1 favored the SSU strategy. Secondary outcomes included 90-day mortality and re-hospitalization, costs, and 1-month days-alive-and-out-of-hospital (DAOOH). Of the 467 articles identified by our search strategy, only 3 full text articles were included. In meta-analysis for the primary outcome of 30-day death or readmission, the RR was 0.95 (95% CI = 0.56 to 1.63; I2 = 0%) for patients randomized to SSU vs hospitalization (2 studies, 241 patients). There were only 2 total deaths at 30 days in the 2 studies (total N = 258) which reported 30-day mortality, both in hospitalized patients. Only one study reported 90-day outcomes, showing no significant differences. Costs were lower in the SSU arm from one study, and 30-day DAOOH also favored SSU based on a single randomized trial. Based on very limited evidence, SSU provides similar efficacy for 30-day and 90-day mortality and readmission compared to hospitalization. An SSU strategy appears safe and may be cost effective.

The utility of urine sodium-guided diuresis during acute decompensated heart failure.

Diuresis to achieve decongestion is a central aim of therapy in patients hospitalized for acute decompensated heart failure (ADHF). While multiple approaches have been tried to achieve adequate decongestion rapidly while minimizing adverse effects, no single diuretic strategy has shown superiority, and there is a paucity of data and guidelines to utilize in making these decisions. Observational cohort studies have shown associations between urine sodium excretion and outcomes after hospitalization for ADHF. Urine chemistries (urine sodium ± urine creatinine) may guide diuretic titration during ADHF, and multiple randomized clinical trials have been designed to compare a strategy of urine chemistry-guided diuresis to usual care. This review will summarize current literature for diuretic monitoring and titration strategies, outline evidence gaps, and describe the recently completed and ongoing clinical trials to address these gaps in patients with ADHF with a particular focus on the utility of urine sodium-guided strategies.

Impact of empagliflozin on decongestion in acute heart failure: the EMPULSE trial.

AIMS: Effective and safe decongestion remains a major goal for optimal management of patients with acute heart failure (AHF). The effects of the sodium-glucose cotransporter 2 inhibitor empagliflozin on decongestion-related endpoints in the EMPULSE trial (NCT0415775) were evaluated. METHODS AND RESULTS: A total of 530 patients hospitalized for AHF were randomized 1:1 to either empagliflozin 10 mg once daily or placebo for 90 days. The outcomes investigated were: weight loss (WL), WL adjusted for mean daily loop diuretic dose (WL-adjusted), area under the curve of change from baseline in N-terminal pro-B-type natriuretic peptide levels, hemoconcentration, and clinical congestion score after 15, 30, and 90 days of treatment. Compared with placebo, patients treated with empagliflozin demonstrated significantly greater reductions in all studied markers of decongestion at all time-points, adjusted mean differences (95% confidence interval) at Days 15, 30, and 90 were: for WL -1.97 (-2.86, -1.08), -1.74 (-2.73, -0.74); -1.53 (-2.75, -0.31) kg; for WL-adjusted: -2.31 (-3.77, -0.85), -2.79 (-5.03, -0.54), -3.18 (-6.08, -0.28) kg/40 mg furosemide i.v. or equivalent; respectively (all P < 0.05). Greater WL at Day 15 (i.e. above the median WL in the entire population) was associated with significantly higher probability for clinical benefit at Day 90 (hierarchical composite of all-cause death, heart failure events, and a 5-point or greater difference in Kansas City Cardiomyopathy Questionnaire total symptom score change from baseline to 90 days) with the win ratio of 1.75 (95% confidence interval 1.37, 2.23; P < 0.0001). CONCLUSION: Initiation of empagliflozin in patients hospitalized for AHF resulted in an early, effective and sustained decongestion which was associated with clinical benefit at Day 90.

Effects of Empagliflozin on Symptoms, Physical Limitations, and Quality of Life in Patients Hospitalized for Acute Heart Failure: Results From the EMPULSE Trial.

BACKGROUND: Patients hospitalized for acute heart failure experience poor health status, including a high burden of symptoms and physical limitations, and poor quality of life. SGLT2 (sodium-glucose cotransporter 2) inhibitors improve health status in chronic heart failure, but their effect on these outcomes in acute heart failure is not well characterized. We investigated the effects of the SGLT2 inhibitor empagliflozin on symptoms, physical limitations, and quality of life, using the Kansas City Cardiomyopathy Questionnaire (KCCQ) in the EMPULSE trial (Empagliflozin in Patients Hospitalized With Acute Heart Failure Who Have Been Stabilized). METHODS: Patients hospitalized for acute heart failure were randomized to empagliflozin 10 mg daily or placebo for 90 days. The KCCQ was assessed at randomization and 15, 30, and 90 days. The effects of empagliflozin on the primary end point of clinical benefit (hierarchical composite of all-cause death, heart failure events, and a 5-point or greater difference in KCCQ Total Symptom Score [TSS] change from baseline to 90 days) were examined post hoc across the tertiles of baseline KCCQ-TSS. In prespecified analyses, changes (randomization to day 90) in KCCQ domains, including TSS, physical limitations, quality of life, clinical summary, and overall summary scores were evaluated using a repeated measures model. RESULTS: In total, 530 patients were randomized (265 each arm). Baseline KCCQ-TSS was low overall (mean [SD], 40.8 [24.0] points). Empagliflozin-treated patients experienced greater clinical benefit across the range of KCCQ-TSS, with no treatment effect heterogeneity (win ratio [95% CIs] from lowest to highest tertile: 1.49 [1.01-2.20], 1.37 [0.94-1.99], and 1.48 [1.00-2.20], respectively; P for interaction=0.94). Beneficial effects of empagliflozin on health status were observed as early as 15 days and persisted through 90 days, at which point empagliflozin-treated patients experienced a greater improvement in KCCQ TSS, physical limitations, quality of life, clinical summary, and overall summary (placebo-adjusted mean differences [95% CI]: 4.45 [95% CI, 0.32-8.59], P=0.03; 4.80 [95% CI, 0.00-9.61], P=0.05; 4.66 [95% CI, 0.32-9.01], P=0.04; 4.85 [95% CI, 0.77-8.92], P=0.02; and 4.40 points [95% CI, 0.33-8.48], P=0.03, respectively). CONCLUSIONS: Initiation of empagliflozin in patients hospitalized for acute heart failure produced clinical benefit regardless of the degree of symptomatic impairment at baseline, and improved symptoms, physical limitations, and quality of life, with benefits seen as early as 15 days and maintained through 90 days. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT0415775.

Randomized controlled trial of urinE chemiStry guided aCute heArt faiLure treATmEnt (ESCALATE): Rationale and design.

Diuresis to achieve decongestion is a central aim of therapy in patients hospitalized for acute decompensated heart failure (ADHF). While multiple clinical trials have investigated initial diuretic strategies for a designated period of time, there is a paucity of evidence to guide diuretic titration strategies continued until decongestion is achieved. The use of urine chemistries (urine sodium and creatinine) in a natriuretic response prediction equation accurately estimates natriuresis in response to diuretic dosing, but a randomized clinical trial is needed to compare a urine chemistry-guided diuresis strategy with a strategy of usual care. The urinE chemiStry guided aCute heArt faiLure treATmEnt (ESCALATE) trial is designed to test the hypothesis that protocolized diuretic therapy guided by spot urine chemistry through completion of intravenous diuresis will be superior to usual care and improve outcomes over the 14 days following randomization. ESCALATE will randomize and obtain complete data on 450 patients with acute heart failure to a diuretic strategy guided by urine chemistry or a usual care strategy. Key inclusion criteria include an objective measure of hypervolemia with at least 10 pounds of estimated excess volume, and key exclusion criteria include significant valvular stenosis, hypotension, and a chronic need for dialysis. Our primary outcome is days of benefit over the 14 days after randomization. Days of benefit combines patient symptoms captured by global clinical status with clinical state quantifying the need for hospitalization and intravenous diuresis. CLINICAL TRIAL REGISTRATION: NCT04481919.

Dosimetric predictors of acute bowel toxicity after Stereotactic Body Radiotherapy (SBRT) in the definitive treatment of localized prostate cancer.

INTRODUCTION: SBRT is an increasingly popular treatment for localized prostate cancer, though considerable variation in technical approach is common and optimal dose constraints are uncertain. In this study, we sought to identify dosimetric and patient-related predictors of acute rectal toxicity. METHODS: Patients included in this study were treated with prostate SBRT on a prospective institutional protocol. Physician-graded toxicity and patient-reported outcomes were captured at one week, one month, and three months following SBRT. DVH data were extracted and converted into relative volume differential DVHs for NTCP modeling. Patient- and disease-related covariates along with NTCP model predictions were independently tested for significant association with physician-graded toxicity or a decline in bowel-related QoL. A multivariate model was constructed using forward selection, and significant parameter cutoff values were obtained with Fischer's exact test to group patients by risk of developing physician-graded toxicity or detriments in patient-reported QoL. RESULTS: One hundred and three patients treated for localized prostate cancer with SBRT were included in our analysis. 52% of patients experienced a clinically significant decline in bowel-related QOL within 1 week of completion of treatment, while only 27.5% of patients developed grade 2+ physician-graded rectal toxicity. Sequential feature selection multivariate logistic regression identified rectal V22.5 Gy (p = 0.001) and D19% (p = 0.001) as independent predictors of clinically significant toxicity, while rectal V20Gy (p = 0.004) and D25.3% (p = 0.007) were independently correlated with physician-graded toxicity. Global multivariate step-wise logistic regression identified only D19% (p = 0.001) and V20Gy (p = 0.004) as independent predictors of acute bowel bother or physician-graded rectal toxicity respectively. CONCLUSIONS: Moderate doses to large rectal volumes, D19% and V20Gy, were associated with an increased incidence of a clinically significant decrease in patient-reported bowel QOL and physician-scored grade 2+ rectal toxicity, respectively. These dosimetric parameters may help practitioners mitigate acute toxicity in patients treated with prostate SBRT.

Global disparities in prescription of guideline-recommended drugs for heart failure with reduced ejection fraction.

BACKGROUND: Heart failure (HF) is a global challenge, with lower- and middle-income countries (LMICs) carrying a large share of the burden. Treatment for HF with reduced ejection fraction (HFrEF) improves survival but is often underused. Economic factors might have an important effect on the use of medicines. METHODS AND RESULTS: This analysis assessed prescription rates and doses of renin-angiotensin system (RAS) inhibitors, ß-blockers, and mineralocorticoid receptor antagonists at discharge and 6-month follow-up in 8669 patients with HFrEF (1458 from low-, 3363 from middle-, and 3848 from high-income countries) hospitalized for acute HF in 44 countries in the prospective REPORT-HF study. We investigated determinants of guideline-recommended treatments and their association with 1-year mortality, correcting for treatment indication bias.Only 37% of patients at discharge and 34% of survivors at 6 months were on all three medication classes, with lower proportions in LMICs than high-income countries (19 vs. 41% at discharge and 15 vs. 37% at 6 months). Women and patients without health insurance, or from LMICs, or without a scheduled medical follow-up within 6 months of discharge were least likely to be on guideline-recommended medical therapy at target doses, independent of confounders. Being on ≥50% of guideline-recommended doses of RAS inhibitors, and ß-blockers were independently associated with better 1-year survival, regardless of country income level. CONCLUSION: Patients with HFrEF in LMICs are less likely to receive guideline-recommended drugs at target doses. Improved access to medications and medical care could reduce international disparities in outcome.

What are the Data for Current Prognostic Tools Used to Determine the Risk of Short-Term Adverse Events in Patients with Acute Heart Failure?

BACKGROUND: Acute heart failure (AHF) is a common condition evaluated in the emergency department (ED). Patients may present with a wide range of signs and symptoms, comorbidities, exacerbating factors, and ability to follow-up. Having a decision tool to objectively assess the risk of near-term events would help guide disposition decisions in these patients. CLINICAL QUESTION: What are the data for current tools used to determine the short-term risk of adverse events of patients with AHF in the ED setting? EVIDENCE REVIEW: Studies retrieved included six prospective studies and three retrospective cohort studies that evaluated the following five different risk scores that may predict the risk of serious adverse events in those with AHF: Ottawa Heart Failure Risk Score (OHFRS), Emergency Heart Failure Mortality Risk Grade (EHMRG), EHMRG at 30 days with addition of an ST depression variable (EHMRG30-ST), Multiple Estimation of Risk Based on the Emergency Department Spanish 40 Score in Patients with AHF Score (MEESSI-AHF), and the Improving Heart Failure Risk Stratification in the ED (STRATIFY) tool. CONCLUSIONS: Based on the available literature, risk scores, including the OHFRS; EHMRG; EHMRG30-ST; MEESSI-AHF; and STRATIFY, can help identify short-term risk of adverse events, but are insufficient in isolation. Clinicians should use these tools in conjunction with other factors, such as the patient's symptom trajectory, hemodynamics, and access to follow-up care.

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.

Medication Discussions With Patients With Cardiovascular Disease in the Emergency Department: An Opportunity for Emergency Nurses to Engage Patients to Support Medication Reconciliation.

INTRODUCTION: This study aimed to investigate the level of patient involvement in medication reconciliation processes and factors associated with that involvement in patients with cardiovascular disease presenting to the emergency department. METHODS: An observational and cross-sectional design was used. Patients with cardiovascular disease presenting to the adult emergency department of an academic medical center completed a structured survey inclusive of patient demographics and measures related to the study concepts. Data abstracted from the electronic health record included the patient's medical history and emergency department visit data. Our multivariable model adjusted for age, gender, education, difficulty paying bills, health status, numeracy, health literacy, and medication knowledge and evaluated patient involvement in medication discussions as an outcome. RESULTS: Participants' (N = 93) median age was 59 years (interquartile range 51-67), 80.6% were white, 96.8% were not Hispanic, and 49.5% were married or living with a partner. Approximately 41% reported being employed and 36.9% reported an annual household income of <$25,000. Almost half (n = 44, 47.3%) reported difficulty paying monthly bills. Patients reported moderate medication knowledge (median 3.8, interquartile range 3.4-4.2) and perceived involvement in their care (41.8 [SD = 9.1]). After controlling for patient characteristics, only difficulty paying monthly bills (b = 0.36, P = .005) and medication knowledge (b = 0.30, P = .009) were associated with involvement in medication discussions. DISCUSSION: Some patients presenting to the emergency department demonstrated moderate medication knowledge and involvement in medication discussions, but more work is needed to engage patients.

A global perspective of racial differences and outcomes in patients presenting with acute heart failure.

Important racial differences in characteristics, treatment, and outcomes of patients with acute heart failure (AHF) have been described. The objective of this analysis of the International Registry to assess medical Practice with longitudinal observation for Treatment of Heart Failure (REPORT-HF) registry was to investigate racial differences in patients with AHF according to country income level.

Current Emergency Department Disposition of Patients With Acute Heart Failure: An Opportunity for Improvement.

Emergency department (ED) providers play a critical role in the stabilization and diagnostic evaluation of patients presenting with acute heart failure (AHF), and EDs are key areas for establishing current best practices and future considerations for the disposition of and decision making for patients with AHF. These elements include accurate risk assessment; response to initial treatment and shared decision making concerning optimal venue of care; reframing of physicians' risk perceptions for patients presenting with AHF; exploration of alternative venues of care beyond hospitalization; population-level changes in demographics, management and outcomes of HF patients; development and testing of data-driven pathways to assist with disposition decisions in the ED; and suggested outcomes for measuring success.

Prostate MRI in Stereotactic Body Radiation Treatment Planning and Delivery for Localized Prostate Cancer.

Prostate MRI is increasingly being used to make diagnoses and guide management for patients receiving definitive radiation treatment for prostate cancer. Radiologists should be familiar with the potential uses of prostate MRI in radiation therapy planning and delivery. Radiation therapy is an established option for the definitive treatment of localized prostate cancer. Stereotactic body radiation therapy (SBRT) is an external-beam radiation therapy method used to deliver a high dose of radiation to an extracranial target in the body, often in five or fewer fractions. SBRT is increasingly being used for prostate cancer treatment and has been recognized by the National Comprehensive Cancer Network as an acceptable definitive treatment regimen for low-, intermediate-, and high-risk prostate cancer. MRI is commonly used to aid in prostate radiation therapy. The authors review the uses of prostate MRI in SBRT treatment planning and delivery. Specific topics discussed include the use of prostate MRI for identification of and dose reduction to the membranous and prostatic urethra, which can decrease the risk of acute and late toxicities. MRI is also useful for identification and appropriate dose coverage of the prostate apex and areas of extraprostatic extension or seminal vesicle invasion. In prospective studies, prostate MRI is being validated for identification of and dose intensification to dominant intraprostatic lesions, which potentially can improve oncologic outcomes. It also can be used to evaluate the placement of fiducial markers and hydrogel spacers for radiation therapy planning and delivery. ©RSNA, 2022.

A pilot study to assess the circulating renin-angiotensin system in COVID-19 acute respiratory failure.

The renin-angiotensin system (RAS) is fundamental to COVID-19 pathobiology, due to the interaction between the SARS-CoV-2 virus and the angiotensin-converting enzyme 2 (ACE2) coreceptor for cellular entry. The prevailing hypothesis is that SARS-CoV-2-ACE2 interactions lead to an imbalance of the RAS, favoring proinflammatory angiotensin II (ANG II)-related signaling at the expense of the anti-inflammatory ANG-(1-7)-mediated alternative pathway. Indeed, multiple clinical trials targeting this pathway in COVID-19 are underway. Therefore, precise measurement of circulating RAS components is critical to understand the interplay of the RAS on COVID-19 outcomes. Multiple challenges exist in measuring the RAS in COVID-19, including improper patient controls, ex vivo degradation and low concentrations of angiotensins, and unvalidated laboratory assays. Here, we conducted a prospective pilot study to enroll 33 patients with moderate and severe COVID-19 and physiologically matched COVID-19-negative controls to quantify the circulating RAS. Our enrollment strategy led to physiological matching of COVID-19-negative and COVID-19-positive moderate hypoxic respiratory failure cohorts, in contrast to the severe COVID-19 cohort, which had increased severity of illness, prolonged intensive care unit (ICU) stay, and increased mortality. Circulating ANG II and ANG-(1-7) levels were measured in the low picomolar (pM) range. We found no significant differences in circulating RAS peptides or peptidases between these three cohorts. The combined moderate and severe COVID-19-positive cohorts demonstrated a mild reduction in ACE activity compared with COVID-19-negative controls (2.2 ± 0.9 × 105 vs. 2.9 ± 0.8 × 105 RFU/mL, P = 0.03). These methods may be useful in designing larger studies to physiologically match patients and quantify the RAS in COVID-19 RAS augmenting clinical trials.

Balanced Crystalloids versus Saline in Noncritically Ill Adults.

BACKGROUND: Comparative clinical effects of balanced crystalloids and saline are uncertain, particularly in noncritically ill patients cared for outside an intensive care unit (ICU). METHODS: We conducted a single-center, pragmatic, multiple-crossover trial comparing balanced crystalloids (lactated Ringer's solution or Plasma-Lyte A) with saline among adults who were treated with intravenous crystalloids in the emergency department and were subsequently hospitalized outside an ICU. The type of crystalloid that was administered in the emergency department was assigned to each patient on the basis of calendar month, with the entire emergency department crossing over between balanced crystalloids and saline monthly during the 16-month trial. The primary outcome was hospital-free days (days alive after discharge before day 28). Secondary outcomes included major adverse kidney events within 30 days - a composite of death from any cause, new renal-replacement therapy, or persistent renal dysfunction (defined as an elevation of the creatinine level to ≥200% of baseline) - all censored at hospital discharge or 30 days, whichever occurred first. RESULTS: A total of 13,347 patients were enrolled, with a median crystalloid volume administered in the emergency department of 1079 ml and 88.3% of the patients exclusively receiving the assigned crystalloid. The number of hospital-free days did not differ between the balanced-crystalloids and saline groups (median, 25 days in each group; adjusted odds ratio with balanced crystalloids, 0.98; 95% confidence interval [CI], 0.92 to 1.04; P=0.41). Balanced crystalloids resulted in a lower incidence of major adverse kidney events within 30 days than saline (4.7% vs. 5.6%; adjusted odds ratio, 0.82; 95% CI, 0.70 to 0.95; P=0.01). CONCLUSIONS: Among noncritically ill adults treated with intravenous fluids in the emergency department, there was no difference in hospital-free days between treatment with balanced crystalloids and treatment with saline. (Funded by the Vanderbilt Institute for Clinical and Translational Research and others; SALT-ED ClinicalTrials.gov number, NCT02614040 .).

Efficacy and safety of dapagliflozin in acute heart failure: Rationale and design of the DICTATE-AHF trial.

BACKGROUND: Dapagliflozin, a sodium-glucose cotransporter-2 inhibitor, reduces cardiovascular death and worsening heart failure in patients with chronic heart failure and reduced ejection fraction. Early initiation during an acute heart failure (AHF) hospitalization may facilitate decongestion, improve natriuresis, and facilitate safe transition to a beneficial outpatient therapy for both diabetes and heart failure. OBJECTIVE: The objective is to assess the efficacy and safety of initiating dapagliflozin within the first 24 hours of hospitalization in patients with AHF compared to usual care. METHODS: DICTATE-AHF is a prospective, multicenter, open-label, randomized trial enrolling a planned 240 patients in the United States. Patients with type 2 diabetes hospitalized with hypervolemic AHF and an estimated glomerular filtration rate of at least 30 mL/min/1.73m2 are eligible for participation. Patients are randomly assigned 1:1 to dapagliflozin 10 mg once daily or structured usual care until day 5 or hospital discharge. Both treatment arms receive protocolized diuretic and insulin therapies. The primary endpoint is diuretic response expressed as the cumulative change in weight per cumulative loop diuretic dose in 40 mg intravenous furosemide equivalents. Secondary and exploratory endpoints include inpatient worsening AHF, 30-day hospital readmission for AHF or diabetic reasons, change in NT-proBNP, and measures of natriuresis. Safety endpoints include the incidence of hyper/hypoglycemia, ketoacidosis, worsening kidney function, hypovolemic hypotension, and inpatient mortality. CONCLUSIONS: The DICTATE-AHF trial will establish the efficacy and safety of early initiation of dapagliflozin during AHF across both AHF and diabetic outcomes in patients with diabetes.

Use of Machine Learning to Develop a Risk-Stratification Tool for Emergency Department Patients With Acute Heart Failure.

STUDY OBJECTIVE: We use variables from a recently derived acute heart failure risk-stratification rule (STRATIFY) as a basis to develop and optimize risk prediction using additional patient clinical data from electronic health records and machine-learning models. METHODS: Using a retrospective cohort design, we identified all emergency department (ED) visits for acute heart failure between January 1, 2017, and December 31, 2018, among adult health plan members of a large system with 21 EDs. The primary outcome was any 30-day serious adverse event, including death, cardiopulmonary resuscitation, balloon-pump insertion, intubation, new dialysis, myocardial infarction, or coronary revascularization. Starting with the 13 variables from the STRATIFY rule (base model), we tested whether predictive accuracy in a different population could be enhanced with additional electronic health record-based variables or machine-learning approaches (compared with logistic regression). We calculated our derived model area under the curve (AUC), calculated test characteristics, and assessed admission rates across risk categories. RESULTS: Among 26,189 total ED encounters, mean patient age was 74 years, 51.7% were women, and 60.7% were white. The overall 30-day serious adverse event rate was 18.8%. The base model had an AUC of 0.76 (95% confidence interval 0.74 to 0.77). Incorporating additional variables led to improved accuracy with logistic regression (AUC 0.80; 95% confidence interval 0.79 to 0.82) and machine learning (AUC 0.85; 95% confidence interval 0.83 to 0.86). We found that 11.1%, 25.7%, and 48.9% of the study population had predicted serious adverse event risk of less than or equal to 3%, less than or equal to 5%, and less than or equal to 10%, respectively, and 28% of those with less than or equal to 3% risk were admitted. CONCLUSION: Use of a machine-learning model with additional variables improved 30-day risk prediction compared with conventional approaches.

Effect of balanced crystalloids versus saline on urinary biomarkers of acute kidney injury in critically ill adults.

BACKGROUND: Recent trials have suggested use of balanced crystalloids may decrease the incidence of major adverse kidney events compared to saline in critically ill adults. The effect of crystalloid composition on biomarkers of early acute kidney injury remains unknown. METHODS: From February 15 to July 15, 2016, we conducted an ancillary study to the Isotonic Solutions and Major Adverse Renal Events Trial (SMART) comparing the effect of balanced crystalloids versus saline on urinary levels of neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1) among 261 consecutively-enrolled critically ill adults admitted from the emergency department to the medical ICU. After informed consent, we collected urine 36 ± 12 h after hospital admission and measured NGAL and KIM-1 levels using commercially available ELISAs. Levels of NGAL and KIM-1 at 36 ± 12 h were compared between patients assigned to balanced crystalloids versus saline using a Mann-Whitney U test. RESULTS: The 131 patients (50.2%) assigned to the balanced crystalloid group and the 130 patients (49.8%) assigned to the saline group were similar at baseline. Urinary NGAL levels were significantly lower in the balanced crystalloid group (median, 39.4 ng/mg [IQR 9.9 to 133.2]) compared with the saline group (median, 64.4 ng/mg [IQR 27.6 to 339.9]) (P < 0.001). Urinary KIM-1 levels did not significantly differ between the balanced crystalloid group (median, 2.7 ng/mg [IQR 1.5 to 4.9]) and the saline group (median, 2.4 ng/mg [IQR 1.3 to 5.0]) (P = 0.36). CONCLUSIONS: In this ancillary analysis of a clinical trial comparing balanced crystalloids to saline among critically ill adults, balanced crystalloids were associated with lower urinary concentrations of NGAL and similar urinary concentrations of KIM-1, compared with saline. These results suggest only a modest reduction in early biomarkers of acute kidney injury with use of balanced crystalloids compared with saline. TRIAL REGISTRATION: ClinicalTrials.gov number: NCT02444988 . Date registered: May 15, 2015.

An emergency care research course for healthcare career preparation.

BACKGROUND: University students have limited opportunities to gain healthcare clinical exposure within an academic curriculum. Furthermore, traditional pre-medical clinical experiences like shadowing lack active learning components. This may make it difficult for students to make an informed decision about pursuing biomedical professions. An academic university level research course with bedside experience provides students direct clinical participation in the healthcare setting. METHODS: Described is a research immersion course for senior university students (3rd to 5th year) interested in healthcare and reported study enrollment with final course evaluations. The setting was an adult, academic, urban, level 1 trauma center emergency department (ED) within a tertiary-care, 1000-bed, medical center. Our course, "Immersion in Emergency Care Research", was offered as a university senior level class delivered consecutively over 16-weeks for students interested in healthcare careers. Faculty and staff from the Department of Emergency Medicine provided a classroom lecture program and extensive bedside, hands-on clinical research experience. Students enrolled patients in a survey study requiring informed consent, interviews, data abstraction and data entry. Additionally, they were required to write and present a mock emergency care research proposal inspired by their clinical experience. The course evaluations from students' ordinal rankings and blinded text responses report possible career impact. RESULTS: Thirty-two students, completed the 16-week, 6-9 h per week, course from August to December in 1 of 4 years (2016 to 2019). Collectively, students enrolled 759 ED patients in the 4 survey studies and reported increased confidence in the clinical research process as each week progressed. Ranked evaluations were extremely positive, with many students describing how the course significantly impacted their career pathways and addressed an unmet need in biomedical education. Six students continued the research experience from the course through independent study using the survey data to develop 3 manuscripts for submission to peer-reviewed journals. CONCLUSIONS: A bedside emergency care research course for students with pre-healthcare career aspirations can successfully provide early exposure to patients and emergency care, allow direct experience with clinical bedside research, research data collection, and may impact biomedical science career choices.