Experiential Learning with Ketamine: A Mixed-Methods Exploratory Study on Prescription and Perception.

Background: Incorporating unfamiliar therapies into practice requires effective longitudinal learning and the optimal way to achieve this is debated. Though not a novel therapy, ketamine in critical care has a paucity of data and variable acceptance, with limited research describing intensivist perceptions and utilization. The Coronavirus-19 pandemic presented a particular crisis where providers rapidly adapted analgosedation strategies to achieve prolonged, deep sedation due to a surge of severe acute respiratory distress syndrome (ARDS). Question: How does clinical experience with ketamine impact the perception and attitude of clinicians toward this therapy? Methods: We conducted a mixed-methods study using quantitative ketamine prescription data and qualitative focus group data. We analyzed prescription patterns of ketamine in a tertiary academic ICU during two different time points: pre-COVID-19 (March 1-June 30, 2019) and during the COVID-19 surge (March 1-June 30, 2020). Two focus groups (FG) of critical care attendings were held, and data were analyzed using the Framework Method for content analysis. Results: Four-hundred forty-six medical ICU patients were mechanically ventilated (195 pre-COVID-19 and 251 during COVID-19). The COVID-19 population was more likely to receive ketamine (81[32.3%] vs 4 [2.1%], p < 0.001). Thirteen respondents participated across two FG sessions (Pre-COVID = 8, Post-COVID=5). The most prevalent attitude among our respondents was discomfort, with three key themes identified as follows: 1) lack of evidence regarding ketamine, 2) lack of personal experience, and 3) desire for more education and protocols. Conclusion: Despite a substantial increase in ketamine prescription during COVID-19, intensivists continued to feel discomfort with utilization. Factors contributing to this discomfort include a lack of evidence, a lack of experience, and a desire for more education and protocols. Increase in experience with ketamine alone was not sufficient to minimize provider discomfort. These findings should inform future curricula and call for process improvement to optimize continuing education.

Evaluation of Clinical Outcomes Associated With Phenobarbital With Taper Compared to No Taper for the Management of Alcohol Withdrawal Syndrome.

BACKGROUND: Phenobarbital (PHB) has been shown to be an effective treatment of alcohol withdrawal syndrome (AWS), with multiple dosing strategies used (e.g., single-dose and symptom-triggered). Studies have often used tapered doses, typically following a front-loaded dose, despite PHB's long half-life which should lead to an ability to auto-taper. OBJECTIVE: The purpose of this study was to compare clinical outcomes associated with two PHB dosing strategies (taper [T], no taper [NT]) for AWS. METHODS: This retrospective cohort study compared adult patients admitted to the ICU from October 2017 to May 2019 who received an initial loading dose of PHB for AWS. The use of PHB was at the discretion of the clinician per our institutional guidelines. Prior to November 2018, patients were prescribed a PHB taper, while after this period, the taper was no longer recommended. The primary outcome was the proportion of patients requiring rescue PHB or adjunctive medications for AWS. Secondary outcomes included number of adjunctive agents used, prevalence of severe manifestations of AWS, ICU and hospital lengths of stay, and incidence of potentially significant drug interactions. RESULTS: A total of 172 patients were included (T: n = 81, NT: n = 91). Baseline characteristics were similar between groups, including history of severe AWS and cumulative benzodiazepine dose pre-PHB. There was no difference in the primary outcome between groups (T: 70.4% vs NT: 59.3%, P = 0.152). The median number of adjunctive agents per patient, severe manifestations, and ICU and hospital length of stay did not differ between groups. Twenty-five patients (14.5%) had potentially significant drug interactions. CONCLUSION AND RELEVANCE: The use of a PHB loading dose without a taper may be comparable to a taper strategy on clinical outcomes. Prospective studies are needed to further delineate the optimal dose of PHB for AWS.

Cardiovascular magnetic resonance characterization of myocardial tissue injury in a miniature swine model of cancer therapy-related cardiovascular toxicity.

BACKGROUND: Left ventricular ejection fraction (LVEF) is the most commonly clinically used imaging parameter for assessing cancer therapy-related cardiac dysfunction (CTRCD). However, LVEF declines may occur late, after substantial injury. This study sought to investigate cardiovascular magnetic resonance (CMR) imaging markers of subclinical cardiac injury in a miniature swine model. METHODS: Female Yucatan miniature swine (n = 14) received doxorubicin (2 mg/kg) every 3 weeks for 4 cycles. CMR, including cine, tissue characterization via T1 and T2 mapping, and late gadolinium enhancement (LGE) were performed on the same day as doxorubicin administration and 3 weeks after the final chemotherapy cycle. In addition, magnetic resonance spectroscopy (MRS) was performed during the 3 weeks after the final chemotherapy in 7 pigs. A single CMR and MRS exam were also performed in 3 Yucatan miniature swine that were age- and weight-matched to the final imaging exam of the doxorubicin-treated swine to serve as controls. CTRCD was defined as histological early morphologic changes, including cytoplasmic vacuolization and myofibrillar loss of myocytes, based on post-mortem analysis of humanely euthanized pigs after the final CMR exam. RESULTS: Of 13 swine completing 5 serial CMR scans, 10 (77%) had histological evidence of CTRCD. Three animals had neither histological evidence nor changes in LVEF from baseline. No absolute LVEF <40% or LGE was observed. Native T1, extracellular volume (ECV), and T2 at 12 weeks were significantly higher in swine with CTRCD than those without CTRCD (1178 ms vs. 1134 ms, p = 0.002, 27.4% vs. 24.5%, p = 0.03, and 38.1 ms vs. 36.4 ms, p = 0.02, respectively). There were no significant changes in strain parameters. The temporal trajectories in native T1, ECV, and T2 in swine with CTRCD showed similar and statistically significant increases. At the same time, there were no differences in their temporal changes between those with and without CTRCD. MRS myocardial triglyceride content substantially differed among controls, swine with and without CTRCD (0.89%, 0.30%, 0.54%, respectively, analysis of variance, p = 0.01), and associated with the severity of histological findings and incidence of vacuolated cardiomyocytes. CONCLUSION: Serial CMR imaging alone has a limited ability to detect histologic CTRCD beyond LVEF. Integrating MRS myocardial triglyceride content may be useful for detection of early potential CTRCD.

OXYGEN CONSUMPTION AS AN EARLY WARNING SYSTEM IN THE CRITICALLY ILL.

ABSTRACT: Introduction: In this study, we assessed whether changes in oxygen consumption (VO 2 ) and other metabolic parameters could be used as an early warning system for detecting clinical deterioration in mechanically ventilated patients. Methods: This was a prospective cohort study of adult patients requiring mechanical ventilation between February 2016 and March 2019. We looked for changes in VO 2 , carbon dioxide production (VCO 2 ), respiratory quotient (RQ), and end-tidal carbon dioxide (EtCO 2 ), occurring prior to clinical deterioration. Clinical deterioration was predefined as a requirement of vasopressor, an increase in serum lactate by 20% where at least one value was above 3 mmol/L, or a decrease in hemoglobin by 20% in the 4 hours prior to clinical deterioration. Results A total of 141 patients were included. There were no detectable changes in VO 2 , VCO 2 , and EtCO 2 within the 4 hours prior to any clinical deterioration. RQ increased significantly within the 4 hours prior to an increase in lactate as compared with no increase in lactate, but there were no detectable changes prior to other clinical deteriorations. Conclusions RQ has the potential to be an early marker of tissue hypoperfusion or mitochondrial dysfunction. However, future studies are necessary to evaluate the use of RQ as a bedside monitor in critical care settings.

Impact of deep learning architectures on accelerated cardiac T1 mapping using MyoMapNet.

The objective of the current study was to investigate the performance of various deep learning (DL) architectures for MyoMapNet, a DL model for T1 estimation using accelerated cardiac T1 mapping from four T1 -weighted images collected after a single inversion pulse (Look-Locker 4 [LL4]). We implemented and tested three DL architectures for MyoMapNet: (a) a fully connected neural network (FC), (b) convolutional neural networks (VGG19, ResNet50), and (c) encoder-decoder networks with skip connections (ResUNet, U-Net). Modified Look-Locker inversion recovery (MOLLI) images from 749 patients at 3 T were used for training, validation, and testing. The first four T1 -weighted images from MOLLI5(3)3 and/or MOLLI4(1)3(1)2 protocols were extracted to create accelerated cardiac T1 mapping data. We also prospectively collected data from 28 subjects using MOLLI and LL4 to further evaluate model performance. Despite rigorous training, conventional VGG19 and ResNet50 models failed to produce anatomically correct T1 maps, and T1 values had significant errors. While ResUNet yielded good quality maps, it significantly underestimated T1 . Both FC and U-Net, however, yielded excellent image quality with good T1 accuracy for both native (FC/U-Net/MOLLI = 1217 ± 64/1208 ± 61/1199 ± 61 ms, all p < 0.05) and postcontrast myocardial T1 (FC/U-Net/MOLLI = 578 ± 57/567 ± 54/574 ± 55 ms, all p < 0.05). In terms of precision, the U-Net model yielded better T1 precision compared with the FC architecture (standard deviation of 61 vs. 67 ms for the myocardium for native [p < 0.05], and 31 vs. 38 ms [p < 0.05], for postcontrast). Similar findings were observed in prospectively collected LL4 data. It was concluded that U-Net and FC DL models in MyoMapNet enable fast myocardial T1 mapping using only four T1 -weighted images collected from a single LL sequence with comparable accuracy. U-Net also provides a slight improvement in precision.

An Explainable Machine Learning Approach Reveals Prognostic Significance of Right Ventricular Dysfunction in Nonischemic Cardiomyopathy.

OBJECTIVES: The authors implemented an explainable machine learning (ML) model to gain insight into the association between cardiac magnetic resonance markers and adverse outcomes of cardiovascular hospitalization and all-cause death (composite endpoint) in patients with nonischemic dilated cardiomyopathy (NICM). BACKGROUND: Risk stratification of patients with NICM remains challenging. An explainable ML model has the potential to provide insight into the contributions of different risk markers in the prediction model. METHODS: An explainable ML model based on extreme gradient boosting (XGBoost) machines was developed using cardiac magnetic resonance and clinical parameters. The study cohorts consist of patients with NICM from 2 academic medical centers: Beth Israel Deaconess Medical Center (BIDMC) and Brigham and Women's Hospital (BWH), with 328 and 214 patients, respectively. XGBoost was trained on 70% of patients from the BIDMC cohort and evaluated based on the other 30% as internal validation. The model was externally validated using the BWH cohort. To investigate the contribution of different features in our risk prediction model, we used Shapley additive explanations (SHAP) analysis. RESULTS: During a mean follow-up duration of 40 months, 34 patients from BIDMC and 33 patients from BWH experienced the composite endpoint. The area under the curve for predicting the composite endpoint was 0.71 for the internal BIDMC validation and 0.69 for the BWH cohort. SHAP analysis identified parameters associated with right ventricular (RV) dysfunction and remodeling as primary markers of adverse outcomes. High risk thresholds were identified by SHAP analysis and thus provided thresholds for top predictive continuous clinical variables. CONCLUSIONS: An explainable ML-based risk prediction model has the potential to identify patients with NICM at risk for cardiovascular hospitalization and all-cause death. RV ejection fraction, end-systolic and end-diastolic volumes (as indicators of RV dysfunction and remodeling) were determined to be major risk markers.

Accelerated cardiac T1 mapping in four heartbeats with inline MyoMapNet: a deep learning-based T1 estimation approach.

PURPOSE: To develop and evaluate MyoMapNet, a rapid myocardial T1 mapping approach that uses fully connected neural networks (FCNN) to estimate T1 values from four T1-weighted images collected after a single inversion pulse in four heartbeats (Look-Locker, LL4). METHOD: We implemented an FCNN for MyoMapNet to estimate T1 values from a reduced number of T1-weighted images and corresponding inversion-recovery times. We studied MyoMapNet performance when trained using native, post-contrast T1, or a combination of both. We also explored the effects of number of T1-weighted images (four and five) for native T1. After rigorous training using in-vivo modified Look-Locker inversion recovery (MOLLI) T1 mapping data of 607 patients, MyoMapNet performance was evaluated using MOLLI T1 data from 61 patients by discarding the additional T1-weighted images. Subsequently, we implemented a prototype MyoMapNet and LL4 on a 3 T scanner. LL4 was used to collect T1 mapping data in 27 subjects with inline T1 map reconstruction by MyoMapNet. The resulting T1 values were compared to MOLLI. RESULTS: MyoMapNet trained using a combination of native and post-contrast T1-weighted images had excellent native and post-contrast T1 accuracy compared to MOLLI. The FCNN model using four T1-weighted images yields similar performance compared to five T1-weighted images, suggesting that four T1 weighted images may be sufficient. The inline implementation of LL4 and MyoMapNet enables successful acquisition and reconstruction of T1 maps on the scanner. Native and post-contrast myocardium T1 by MOLLI and MyoMapNet was 1170 ± 55 ms vs. 1183 ± 57 ms (P = 0.03), and 645 ± 26 ms vs. 630 ± 30 ms (P = 0.60), and native and post-contrast blood T1 was 1820 ± 29 ms vs. 1854 ± 34 ms (P = 0.14), and 508 ± 9 ms vs. 514 ± 15 ms (P = 0.02), respectively. CONCLUSION: A FCNN, trained using MOLLI data, can estimate T1 values from only four T1-weighted images. MyoMapNet enables myocardial T1 mapping in four heartbeats with similar accuracy as MOLLI with inline map reconstruction.

A Retrospective Comparison of the Effectiveness and Safety of Intravenous Olanzapine Versus Intravenous Haloperidol for Agitation in Adult Intensive Care Unit Patients.

OBJECTIVE: Intravenous (IV) olanzapine could be an alternative to first-generation antipsychotics for the management of agitation in intensive care unit (ICU) patients. We compared the effectiveness and safety of IV olanzapine to IV haloperidol for agitation management in adult patients in the ICU at a tertiary academic medical center. METHODS: A retrospective cohort study was conducted. The primary outcome was the proportion of patients who achieved a Richmond Agitation Sedation Scale (RASS) score of < +1 within 4 hours of IV olanzapine or IV haloperidol administration. Secondary outcomes included the proportion of patients who required rescue medications for agitation within 4 hours of initial IV olanzapine or IV haloperidol administration, incidence of adverse events and ICU length of stay. RESULTS: In the 192 patient analytic cohort, there was no difference in the proportion of patients who achieved a RASS score of < +1 within 4 hours of receiving IV olanzapine or IV haloperidol (49% vs. 42%, p = 0.31). Patients in the IV haloperidol group were more likely to receive rescue medications (28% vs 55%, p < 0.01). There was no difference in the incidence of respiratory events or hypotension between IV olanzapine and IV haloperidol. Patients in the IV olanzapine group experienced more bradycardia (11% vs. 3%, p = 0.04) and somnolence (9% vs. 1%, p = 0.02) compared to the IV haloperidol group. Patients in the IV olanzapine group had a longer median ICU length of stay (7.5 days vs. 5 days, p = 0.04). CONCLUSION: In this retrospective cohort study, there was no difference in the effectiveness of IV olanzapine compared to IV haloperidol for the management of agitation. IV olanzapine was associated with an increased incidence of bradycardia and somnolence.

Adherence to oral oncolytics filled through an internal health-system specialty pharmacy compared with external specialty pharmacies.

BACKGROUND: Oral oncolytics are becoming increasingly common in the treatment of solid and hematological malignancies. Medication adherence is especially important to ensure adequate drug levels to treat active malignancies, notably in curative-intent therapy. Further data are needed to quantify and confirm the effects of internal health-system specialty pharmacies (HSSPs) on medication adherence. OBJECTIVE: To confirm the effect of an internal HSSP compared with external specialty pharmacies on oncolytic adherence as measured by proportion of days covered (PDC), medication possession ratio (MPR), and time to treatment (TTT). METHODS: This single-center retrospective cohort study included patients receiving oral oncolytics through an internal HSSP or external specialty pharmacies between January 2019 and June 2020. Fill data were extracted from pharmacy claims databases and electronic medical records. The primary adherence outcome was patient-level PDC. Secondary adherence outcomes included patient-level MPR and TTT. For PDC and MPR analyses, patients with at least 3 fills per oncolytic were included. All patients were included for the TTT analysis. Chi-square or Fisher's exact tests were used to analyze categorical differences between pharmacy groups. Differences in continuous variables across pharmacy groups were evaluated using Wilcoxon rank-sum tests. RESULTS: 871 prescriptions met inclusion criteria: 549 patients were included in the PDC/MPR analysis, and 758 patients were included in the TTT analysis (patients might have multiple prescriptions). Patients who filled at an internal HSSP had a higher median PDC compared with those who filled at external specialty pharmacies (0.99 [IQR = 0.89-1.00] vs 0.91 [IQR = 0.76-0.98]; P < 0.01). The adherence rate as measured by MPR was higher for patients who used an internal HSSP compared with those who used external specialty pharmacies (MPR = 1.00 [IQR = 0.90-1.00] vs 0.93 [IQR = 0.76-1.00]; P < 0.01). Median TTT was lower for patients using the internal HSSP vs an external specialty pharmacy (5 days [IQR = 2-13] vs 27 days [IQR = 2-82], respectively; P < 0.01). CONCLUSIONS: Internal HSSP services improved adherence as measured by PDC and MPR. Significantly lower TTT was seen with the internal HSSP compared with external pharmacies. These data confirm and support use of internal HSSPs to dispense oral oncolytics for treatment of solid and hematological malignancies. DISCLOSURES: This study received no financial support. The authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Trends over time in drug administration during pediatric in-hospital cardiac arrest in the United States.

AIMS: To describe trends in pediatric in-hospital cardiac arrest drug administration and to assess temporal associations of the Pediatric Advanced Life Support (PALS) guideline changes with drug usage. METHODS: Pediatric patients <18 years old with in-hospital cardiac arrest recorded in the American Heart Association Get With The Guidelines-Resuscitation database between 2002 and 2018 were included. The annual adjusted odds of receiving each intra-arrest medication was determined. The association between changes in the PALS Guidelines and medication use over time was assessed interrupted time series analyses. RESULTS: A total of 6107 patients were analyzed. The adjusted odds of receiving lidocaine (0.33; 95% CI, 0.18, 0.61; p < 0.001), atropine (0.19; 95% CI 0.12, 0.30; p < 0.001) and bicarbonate (0.54; 95% CI 0.35, 0.86; p = 0.009) were lower in 2018 compared to 2002. For lidocaine, there were no significant changes in the step (-2.1%; 95% CI, -5.9%, 1.6%; p = 0.27) after the 2010 or 2015 (Step: -1.5%; 95% CI, -8.0%, 5.0; p = 0.65) guideline releases. There were no significant changes in the step for bicarbonate (-2.3%; 95% CI, -7.6%, 3.0%; p = 0.39) after the 2010 updates. For atropine, there was a downward step change after the 2010 guideline release (-5.9%; 95% CI, -10.5%, -1.3%; p = 0.01). CONCLUSIONS: Changes to the PALS guidelines for lidocaine and bicarbonate were not temporally associated with acute changes in the use of these medications; however, better alignment with these updates was observed over time. A minor update to the language surrounding atropine in the PALS text was associated with a modest acute change in the observed use of atropine. Future studies exploring other factors that influence prescribers in pediatric IHCA are needed.

Association Between the Oxygen Consumption: Lactate Ratio and Survival in Critically Ill Patients With Sepsis.

INTRODUCTION: Mitochondrial dysfunction leading to impairment of oxygen extraction, referred to as cytopathic hypoxia, contributes to morbidity in sepsis. Oxygen consumption (VO2) may be a useful measure of the severity of cytopathic hypoxia. We monitored VO2 and carbon dioxide production (VCO2) in septic patients and investigated the association with hospital survival. METHODS: We retrospectively identified adult (≥18 years) septic patients from a larger prospective observational cohort of critically ill patients on mechanical ventilation. A gas-exchange monitor recorded continuous VO2 and VCO2 for up to 48 h. We then tested the association of median VO2, VCO2, respiratory quotient (RQ), and the VO2:lactate ratio with survival. RESULTS: A total of 46 septic patients were included in the analysis, of whom 28 (61%) survived. Overall median VO2 was not associated with survival (3.72 mL/kg/min [IQR: 3.39, 4.92] in survivors and 3.42 mL/kg/min [IQR: 2.97, 5.26] in non-survivors, P = 0.12). The overall median VCO2 and RQ were also not associated with survival. Adjusting for age and the presence of shock did not change these results. The VO2:lactate ratio was associated with survival (adjusted OR 2.17 [95% CI 1.12, 4.22] per unit increase in ratio, P = 0.03). The percent change in median VCO2 was 11.6% [IQR: -8.2, 28.7] in survivors compared with -8.3% [IQR: -18.0, 4.7] in non-survivors (P = 0.03). The percent changes in median VO2 and RQ were not different between groups. CONCLUSION: The VO2:lactate ratio was significantly higher in survivors, while there was no association between median VO2 alone and survival. There was a significant difference in change in VCO2 over time between survivors and non-survivors.

Lactate and hypotension as predictors of mortality after in-hospital cardiac arrest.

AIM: Guidance on post-cardiac arrest prognostication is largely based on data from out-of-hospital cardiac arrest (OHCA), despite clear differences between the OHCA and in-hospital cardiac arrest (IHCA) populations. Early prediction of mortality after IHCA would be useful to help make decisions about post-arrest care. We evaluated the ability of lactate and need for vasopressors after IHCA to predict hospital mortality. METHODS: Single center retrospective observational study of adult IHCA patients who achieved sustained return of spontaneous circulation (ROSC), required mechanical ventilation peri-arrest and had a lactate checked within 2 h after ROSC. We evaluated the association of post-ROSC lactate and need for vasopressors with mortality using multivariate logistic regression. RESULTS: A total of 364 patients were included. Patients who received vasopressors within 3 h after ROSC had significantly higher mortality compared to patients who did not receive vasopressors (58% vs. 43%, p = 0.03). Elevated lactate level was associated with mortality (44% if lactate <5 mmol/L, 58% if lactate 5-10 mmol/L, and 73% if lactate >10 mmol/L, p < 0.01). A multivariable model with lactate group and post-ROSC vasopressor use as predictors demonstrated moderate discrimination (AUC 0.64 [95%CI:0.59-0.70]). Including other variables, the most parsimonious model included lactate, age, body mass index, race, and history of arrhythmia, cancer and/or liver disease (AUC 0.70 [95% CI: 0.64-0.75]). CONCLUSION: Post-ROSC lactate and need for vasopressors may be helpful in stratifying mortality risk in patients requiring mechanical ventilation after IHCA.

Weight-Based Dosing Versus a Fixed-Dose Regimen of 4-Factor Prothrombin Complex Concentrate in Obese Patients Requiring Vitamin K Antagonist Reversal.

INTRODUCTION: Despite an increase in the use of fixed-dose protocols of 4-factor prothrombin complex concentrate (4F-PCC) for the reversal of vitamin K antagonists (VKAs), there remains a paucity of data in obese patients. In this study, we aimed to compare the proportion of patients attaining international normalized ratio (INR) goals using a weight-based dosing strategy versus a fixed-dose regimen of 4F-PCC. METHODS: This was a retrospective study conducted in patients 18 years of age or older, weighing ≥ 100 kg, who received either a weight-based dose or fixed dose of 4F-PCC (2000 units) for the reversal of VKA, and had a documented baseline and post-treatment INR. The primary outcome was the proportion of patients achieving an INR of < 2 for all indications of warfarin reversal, except in patients with intracranial hemorrhage, where the goal was an INR of < 1.5. RESULTS: A total of 44 patients met the inclusion criteria; 25 patients in the weight-based dosing group and 19 patients in the fixed-dose group. The median baseline INR was similar in both groups (weight-based dosing group 3.2 [interquartile range {IQR} 2.8-3.7] vs fixed-dose group 3.0 [IQR 2.7-4.9], p = 1). The median post-treatment INR was significantly lower in the weight-based dosing group compared to the fixed-dose group (1.3 [IQR 1.2-1.5] vs 1.6 [IQR 1.5-1.9], p < 0.01). However, there was no significant difference in the primary outcome between both groups (weight-based dosing strategy 84% vs fixed dose strategy 90%, p = 0.68). CONCLUSION: Our findings suggest that a fixed-dose regimen of 2000 units in obese patients weighing ≥ 100 kg is adequate to achieve these INR goals.

Epinephrine in children receiving cardiopulmonary resuscitation for bradycardia with poor perfusion.

AIM: To determine whether the use of epinephrine in pediatric patients receiving cardiopulmonary resuscitation for bradycardia and poor perfusion was associated with improved clinical outcomes. METHODS: Using the Get With The Guidelines-Resuscitation registry, we included pediatric patients (≤18 years) who received in-hospital cardiopulmonary resuscitation for bradycardia with poor perfusion (non-pulseless event) between January 2000 and December 2018. Time-dependent propensity score matching was used to match patients receiving epinephrine within the first 10 min of resuscitation to patients at risk of receiving epinephrine within the same minute. RESULTS: In the full cohort, 55% of patients were male and 39% were neonates. A higher number of patients receiving epinephrine required vasopressors and mechanical ventilation prior to the event compared to those not receiving epinephrine. A total of 3528 patients who received epinephrine were matched to 3528 patients at risk of receiving epinephrine based on the propensity score. Epinephrine was associated with decreased survival to hospital discharge (RR, 0.79 [95% CI, 0.74-0.85]; p < 0.001), return of spontaneous circulation (RR, 0.94 [95% CI, 0,91-0.96]; p < 0.001), 24-h survival (RR, 0.85 [95% CI, 0.81-0.90]; p < 0.001), and favorable neurological outcome (RR, 0.76 [95% CI, 0.68-0.84]; p < 0.001). Epinephrine was also associated with an increased risk of progression to pulselessness (RR, 1.17 [95% CI, 1.06-1.28]; p < 0.001). CONCLUSION: In children receiving cardiopulmonary resuscitation for bradycardia with poor perfusion, epinephrine was associated with worse outcomes, although the study does not eliminate the potential for confounding.

Use of SOFA score in cardiac arrest research: A scoping review.

BACKGROUND: The Sequential Organ Failure Assessment (SOFA) score is a commonly used severity-of-illness score in cardiac arrest research. Due to its nature, the SOFA score often has missing data. How much data is missing and how that missing data is handled is unknown. OBJECTIVES: We conducted a scoping review on cardiac arrest studies using SOFA, focusing on missing data. DATA SOURCES: PubMed, Embase, and Web of Science. STUDY SELECTION: All English-language peer-reviewed studies of cardiac arrest with SOFA as an outcome or exposure were included. DATA EXTRACTION: For each study, quantity of missing SOFA data, analytic strategy to handle missing SOFA variables, whether/to what degree mortality influenced the amount of missing SOFA scores), SOFA score modifications, and number of SOFA measurements was extracted. DATA SYNTHESIS: We included 66 studies published between 2006-2019. Five studies were randomized controlled trials, 26 were prospective cohort studies, and 25 were retrospective cohort studies. SOFA was used as an outcome in 36 (55%) and a primary outcome in 10 (15%). Nine studies (14%) mentioned the quantity of missing SOFA data, which ranged from 0 to 76% (median: 10% [IQR: 6%, 42%]). Twenty-seven (41%) studies reported a method to handle missing SOFA. The most common method used excluded subjects with missing data (81%). In the 50 studies using serial SOFA scores, 11 (22%) documented mortality prior to SOFA measurement; which ranged from 3% to 76% (median: 12% [IQR: 6%-35%]). CONCLUSIONS: Missing data is common in cardiac arrest research using SOFA scores. Variability exists in reporting and handling missing SOFA variables.

Predicting Outcome After Out-of-Hospital Cardiac Arrest: Lactate, Need for Vasopressors, and Cytochrome c.

BACKGROUND: Outcome prediction after out-of-hospital cardiac arrest (OHCA) is difficult. We hypothesized that lactate and need for vasopressors would predict outcome, and that addition of a mitochondrial biomarker would enhance performance of the tool. METHODS: Prospective observational study of OHCA patients presenting to an academic medical center September 2008 to April 2016. We conducted univariate and multivariate logistic regressions. RESULTS: Patients were divided based on 2 variables: vasopressor status and initial lactate (<5 mmol/L, 5-10, ≥10). Three hundred fifty-two patients were evaluated; 249 had a lactate within 3 hours and were included. Patients on vasopressors had higher mortality (74% vs 40%; P < .001). A stepwise increase in mortality is associated with increasing lactate (45% lactate <5, 66% 5-10, and 83% ≥10; P < 001). Multivariable models with lactate group and vasopressors as predictors demonstrated excellent discrimination (area under the receiver operating curve [AUC]: 0.73 [95% confidence interval, CI: 0.66-0.79]; adjusted for additional covariates: AUC: 0.81 [95% CI: 0.75-0.86]). Thirty-six patients had cytochrome c levels available; among these 36, when comparing models with and without cytochrome c, there was no difference (AUC: 0.88 [95% CI: 0.76-1.00] vs AUC: 0.85 [95% CI: 0.73-0.98], respectively; P = .30). CONCLUSION: In this prospective validation, the combination of lactate and vasopressors in the immediate postarrest period is predictive of mortality. Cytochrome c offered minimal additional predictive power.

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.

Ascorbic Acid, Corticosteroids and Thiamine in Sepsis (ACTS) protocol and statistical analysis plan: a prospective, multicentre, double-blind, randomised, placebo-controlled clinical trial.

INTRODUCTION: Septic shock is a common and highly morbid condition. To date, there is no specific therapy proven to attenuate organ injury in septic shock. Recent studies have suggested a role for the combination of ascorbic acid, corticosteroids and thiamine, although randomised data are lacking. METHODS AND ANALYSIS: The Ascorbic Acid, Corticosteroids, and Thiamine in Sepsis trial is a multi-centre, double-blind, randomised, placebo-controlled clinical trial that aims to determine the impact of ascorbic acid, corticosteroids and thiamine versus placebo on organ injury and mortality in patients with septic shock. Patients are randomised to receive 1500 mg of ascorbic acid, 100 mg of thiamine and 50 mg of hydrocortisone parenterally versus matching placebo every 6 hours for 4 days. Clinical and laboratory data are collected at the time of study enrolment, at 24, 72 and 120 hours. The primary end-point for the trial is change in the Sequential Organ Failure Assessment score between enrolment and 72 hours. Additional key secondary outcomes include the incidence of renal failure and 30-day mortality. ETHICS AND DISSEMINATION: The study was approved by the international review board of each participating study site. Study findings will be disseminated through peer-reviewed publications and conference presentations. TRIAL REGISTRATION NUMBER: The trial is registered on clinicaltrials.gov (NCT03389555). It was posted on 3 January 2018.

Annual Incidence of Adult and Pediatric In-Hospital Cardiac Arrest in the United States

BACKGROUND: Previous incidence estimates may no longer reflect the current public health burden of cardiac arrest in hospitalized adult and pediatric patients across the United States. The aim of this study was to estimate the contemporary annual incidence of in-hospital cardiac arrest in adults and children across the United States and to describe trends in incidence between 2008 and 2017. METHODS AND RESULTS: Using the Get With The Guidelines­ Resuscitation registry, we developed a negative binomial regression model to estimate the incidence of index pulseless in-hospital cardiac arrest based on hospital-level characteristics. The model was used to predict the number of in-hospital cardiac arrests in all US hospitals, using data from the American Hospital Association Annual Survey. We performed separate analyses for adult (≥18 years) and pediatric (<18 years) cardiac arrests. Additional analyses were performed for recurrent cardiac arrests and pediatric patients requiring cardiopulmonary resuscitation for poor perfusion (nonpulseless events). The average annual incidence of in-hospital cardiac arrest in the United States was estimated at 292 000 (95% prediction interval, 217 600­503 500) adult and 15 200 pediatric cases, of which 7100 (95% prediction interval, 4400­9900) cases were pulseless cardiac arrests and 8100 (95% prediction interval, 4700­11 500) cases were nonpulseless events. The rate of adult cardiac arrests increased over time, while pediatric events remained more stable. When including both index and recurrent inhospital cardiac arrests, the average annual incidence was estimated at 357 900 (95% prediction interval, 247 100­598 400) adult and 19 900 pediatric cases, of which 8300 (95% prediction interval, 4900­11 200) cases were pulseless cardiac arrests and 11 600 (95% prediction interval, 6400­16 700) cases were nonpulseless events. CONCLUSIONS: There are ≈292 000 adult in-hospital cardiac arrests and 15 200 pediatric in-hospital events in the United States each year. This study provides contemporary estimates of the public health burden of cardiac arrest among hospitalized patients.