Lipidomic changes in a novel sepsis outcome-based analysis reveals potent pro-inflammatory and pro-resolving signaling lipids.

The purpose of this study was to investigate changes in the lipidome of patients with sepsis to identify signaling lipids associated with poor outcomes that could be linked to future therapies. Adult patients with sepsis were enrolled within 24h of sepsis recognition. Patients meeting Sepsis-3 criteria were enrolled from the emergency department or intensive care unit and blood samples were obtained. Clinical data were collected and outcomes of rapid recovery, chronic critical illness (CCI), or early death were adjudicated by clinicians. Lipidomic analysis was performed on two platforms, the Sciex™ 5500 device to perform a lipidomic screen of 1450 lipid species and a targeted signaling lipid panel using liquid-chromatography tandem mass spectrometry. For the lipidomic screen, there were 274 patients with sepsis: 192 with rapid recovery, 47 with CCI, and 35 with early deaths. CCI and early death patients were grouped together for analysis. Fatty acid (FA) 12:0 was decreased in CCI/early death, whereas FA 17:0 and 20:1 were elevated in CCI/early death, compared to rapid recovery patients. For the signaling lipid panel analysis, there were 262 patients with sepsis: 189 with rapid recovery, 45 with CCI, and 28 with early death. Pro-inflammatory signaling lipids from ω-6 poly-unsaturated fatty acids (PUFAs), including 15-hydroxyeicosatetraenoic (HETE), 12-HETE, and 11-HETE (oxidation products of arachidonic acid [AA]) were elevated in CCI/early death patients compared to rapid recovery. The pro-resolving lipid mediator from ω-3 PUFAs, 14(S)-hydroxy docosahexaenoic acid (14S-HDHA), was also elevated in CCI/early death compared to rapid recovery. Signaling lipids of the AA pathway were elevated in poor-outcome patients with sepsis and may serve as targets for future therapies.

Early Physician Gestalt Versus Usual Screening Tools for the Prediction of Sepsis in Critically Ill Emergency Patients.

STUDY OBJECTIVE: Compare physician gestalt to existing screening tools for identifying sepsis in the initial minutes of presentation when time-sensitive treatments must be initiated. METHODS: This prospective observational study conducted with consecutive encounter sampling took place in the emergency department (ED) of an academic, urban, safety net hospital between September 2020 and May 2022. The study population included ED patients who were critically ill, excluding traumas, transfers, and self-evident diagnoses. Emergency physician gestalt was measured using a visual analog scale (VAS) from 0 to 100 at 15 and 60 minutes after patient arrival. The primary outcome was an explicit sepsis hospital discharge diagnosis. Clinical data were recorded for up to 3 hours to compare Systemic Inflammatory Response Syndrome (SIRS), Sequential Organ Failure Assessment (SOFA), quick SOFA (qSOFA), Modified Early Warning Score (MEWS), and a logistic regression machine learning model using Least Absolute Shrinkage and Selection Operator (LASSO) for variable selection. The screening tools were compared using receiver operating characteristic analysis and area under the curve calculation (AUC). RESULTS: A total of 2,484 patient-physician encounters involving 59 attending physicians were analyzed. Two hundred seventy-five patients (11%) received an explicit sepsis discharge diagnosis. When limited to available data at 15 minutes, initial VAS (AUC 0.90; 95% confidence interval [CI] 0.88, 0.92) outperformed all tools including LASSO (0.84; 95% CI 0.82 to 0.87), qSOFA (0.67; 95% CI 0.64 to 0.71), SIRS (0.67; 95% 0.64 to 0.70), SOFA (0.67; 95% CI 0.63 to 0.70), and MEWS (0.66; 95% CI 0.64 to 0.69). Expanding to data available at 60 minutes did not meaningfully change results. CONCLUSION: Among adults presenting to an ED with an undifferentiated critical illness, physician gestalt in the first 15 minutes of the encounter outperformed other screening methods in identifying sepsis.

The Lipid Intensive Drug Therapy for Sepsis Phase II Pilot Clinical Trial.

OBJECTIVES: Low cholesterol levels in early sepsis patients are associated with mortality. We sought to test if IV lipid emulsion administration to sepsis patients with low cholesterol levels would prevent a decline or increase total cholesterol levels at 48 hours. DESIGN: Phase II, adaptive, randomized pilot clinical trial powered for 48 patients. SETTING: Emergency department or ICU of an academic medical center. PATIENTS: Sepsis patients (first 24 hr) with Sequential Organ Failure Assessment greater than or equal to 4 or shock. INTERVENTIONS: Patients meeting study criteria, including screening total cholesterol levels less than or equal to 100 mg/dL or high-density lipoprotein cholesterol (HDL-C) + low-density lipoprotein cholesterol (LDL-C) less than or equal to 70 mg/dL, were randomized to receive one of three doses of lipid emulsion administered twice in 48 hours or no drug (controls). The primary endpoint was a change in serum total cholesterol (48 hr - enrollment) between groups. MEASUREMENTS AND MAIN RESULTS: Forty-nine patients were enrolled and randomized. Two patients randomized to lipid emulsion were withdrawn before drug administration. Data for 24 control patients and 23 lipid emulsion patients were analyzed. The mean change in total cholesterol from enrollment to 48 hours was not different between groups and was 5 mg/dL ( sd 20) for lipid emulsion patients, and 2 mg/dL ( sd 18) for control patients ( p = 0.62). The mean changes in HDL-C and LDL-C were similar between groups. Mean change in triglycerides was elevated in lipid emulsion patients (61 mg/dL, sd 87) compared with controls (20 mg/dL, sd 70, p = 0.086). The 48-hour change in SOFA score was -2 (interquartile range [IQR] -4, -1) for control patients and -2 (IQR -3, 0) for lipid emulsion patients ( p = 0.46). CONCLUSIONS: Administration of IV lipid emulsion to early sepsis patients with low cholesterol levels did not influence change in cholesterol levels from enrollment to 48 hours.

TRENDS IN CHOLESTEROL AND LIPOPROTEINS ARE ASSOCIATED WITH ACUTE RESPIRATORY DISTRESS SYNDROME INCIDENCE AND DEATH AMONG SEPSIS PATIENTS.

ABSTRACT: Objective: Compare changes in cholesterol and lipoprotein levels occurring in septic patients with and without acute respiratory distress syndrome (ARDS) and by survivorship. Methods: We reanalyzed data from prospective sepsis studies. Cholesterol and lipoprotein levels were analyzed using univariate testing to detect changes between septic patients with or without ARDS, and among ARDS survivors compared with nonsurvivors at enrollment (first 24 h of sepsis) and 48 to 72 h later. Results: 214 patients with sepsis were included of whom 48 had ARDS and 166 did not have ARDS. Cholesterol and lipoproteins among septic ARDS versus non-ARDS showed similar enrollment levels. However, 48 to 72 h after enrollment, change in median total cholesterol (48/72 h - enrollment) was significantly different between septic ARDS (-4, interquartile range [IQR] -23.5, 6.5, n = 35) and non-ARDS (0, -10.0, 17.5, P = 0.04; n = 106). When compared by ARDS survivorship, ARDS nonsurvivors (n = 14) had lower median total cholesterol levels (75.5, IQR 68.4, 93.5) compared with ARDS survivors (113.0, IQR 84.0, 126.8, P = 0.022), and lower median enrollment low-density lipoprotein cholesterol (LDL-C) levels (27, IQR 19.5-34.5) compared with ARDS survivors (43, IQR 27-67, P = 0.013; n = 33). Apolipoprotein A-I levels were also significantly lower in ARDS nonsurvivors (n = 14) (87.6, IQR 76.45-103.64) compared with ARDS survivors (130.0, IQR 73.25-165.47, P = 0.047; n = 33). At 48 to 72 h, for ARDS nonsurvivors, median levels of low-density lipoprotein cholesterol (9.0, IQR 4.3, 18.0; n = 10), LDL-C (17.0, IQR 5.0, 29.0; n = 9), and total cholesterol (59.0, 45.3, 81.5; n = 10) were significantly lower compared with ARDS survivors' (n = 25) levels of low-density lipoprotein cholesterol (20.0, IQR 12.0-39.0, P = 0.014), LDL-C (42.0, IQR 27.0-58.0, P = 0.019), and total cholesterol (105.0, IQR 91.0, 115.0, P = 0.003). Conclusions: Change in total cholesterol was different in septic ARDS versus non-ARDS. Total cholesterol, LDL-C, and apolipoprotein A-I levels were lower in ARDS nonsurvivors compared with survivors. Future studies of dysregulated cholesterol metabolism in septic ARDS patients are needed to understand biology and links to potential therapies.

Association of Early Serum Phosphate Levels and Mortality in Patients with Sepsis.

BACKGROUND: Metabolic derangements in sepsis influence phosphate levels, which may predict mortality outcomes. We investigated the association between initial phosphate levels and 28-day mortality in patients with sepsis. METHODS: We conducted a retrospective analysis of patients with sepsis. Initial (first 24 hours) phosphate levels were divided into phosphate quartile groups for comparisons. We used repeated-measures mixed-models to assess differences in 28-day mortality across the phosphate groups, adjusting for other predictors identified by the Least Absolute Shrinkage and Selection Operator variable selection technique. RESULTS: A total of 1,855 patients were included with 13% overall 28-day mortality (n=237). The highest phosphate quartile (>4.0 milligrams per deciliter [mg/dL]) had a higher mortality rate (28%) than the three lower quartiles (P<0.001). After adjustment (age, organ failure, vasopressor administration, liver disease), the highest initial phosphate was associated with increased odds of 28-day mortality. Patients in the highest phosphate quartile had 2.4 times higher odds of death than the lowest (≤2.6 mg/dL) quartile (P<0.01), 2.6 times higher than the second (2.6-3.2 mg/dL) quartile (P<0.01), and 2.0 times higher than the third (3.2-4.0 mg/dL) quartile (P=0.04). CONCLUSION: Septic patients with the highest phosphate levels had increased odds of mortality. Hyperphosphatemia may be an early indicator of disease severity and risk of adverse outcomes from sepsis.

DHCR7 Expression Predicts Poor Outcomes and Mortality From Sepsis.

This is a study of lipid metabolic gene expression patterns to discover precision medicine for sepsis. OBJECTIVES: Sepsis patients experience poor outcomes including chronic critical illness (CCI) or early death (within 14 d). We investigated lipid metabolic gene expression differences by outcome to discover therapeutic targets. DESIGN SETTING AND PARTICITPANTS: Secondary analysis of samples from prospectively enrolled sepsis patients (first 24 hr) and a zebrafish endotoxemia model for drug discovery. Patients were enrolled from the emergency department or ICU at an urban teaching hospital. Enrollment samples from sepsis patients were analyzed. Clinical data and cholesterol levels were recorded. Leukocytes were processed for RNA sequencing and reverse transcriptase polymerase chain reaction. A lipopolysaccharide zebrafish endotoxemia model was used for confirmation of human transcriptomic findings and drug discovery. MAIN OUTCOMES AND MEASURES: The derivation cohort included 96 patients and controls (12 early death, 13 CCI, 51 rapid recovery, and 20 controls) and the validation cohort had 52 patients (6 early death, 8 CCI, and 38 rapid recovery). RESULTS: The cholesterol metabolism gene 7-dehydrocholesterol reductase (DHCR7) was significantly up-regulated in both derivation and validation cohorts in poor outcome sepsis compared with rapid recovery patients and in 90-day nonsurvivors (validation only) and validated using RT-qPCR analysis. Our zebrafish sepsis model showed up-regulation of dhcr7 and several of the same lipid genes up-regulated in poor outcome human sepsis (dhcr24, sqlea, cyp51, msmo1, and ldlra) compared with controls. We then tested six lipid-based drugs in the zebrafish endotoxemia model. Of these, only the Dhcr7 inhibitor AY9944 completely rescued zebrafish from lipopolysaccharide death in a model with 100% lethality. CONCLUSIONS: DHCR7, an important cholesterol metabolism gene, was up-regulated in poor outcome sepsis patients warranting external validation. This pathway may serve as a potential therapeutic target to improve sepsis outcomes.

DHCR7 Expression Predicts Poor Outcomes and Mortality from Sepsis.

Objective: Sepsis patients experience poor outcomes including chronic critical illness (CCI) or early death (within 14 days). We investigated lipid metabolic gene expression differences by outcome to discover therapeutic targets. Design: Secondary analysis of samples from prospectively enrolled sepsis patients and a zebrafish sepsis model for drug discovery. Setting: Emergency department or ICU at an urban teaching hospital. Patients: Sepsis patients presenting within 24 hours. Methods: Enrollment samples from sepsis patients were analyzed. Clinical data and cholesterol levels were recorded. Leukocytes were processed for RNA sequencing (RNA-seq) and reverse transcriptase polymerase chain reaction (RT-qPCR). A lipopolysaccharide (LPS) zebrafish sepsis model was used for confirmation of human transcriptomic findings and drug discovery. Measurements and Main Results: There were 96 samples in the derivation (76 sepsis, 20 controls) and 52 in the validation cohort (sepsis only). The cholesterol metabolism gene 7-Dehydrocholesterol Reductase ( DHCR7) was significantly upregulated in both derivation and validation cohorts in poor outcome sepsis compared to rapid recovery patients and in 90-day non-survivors (validation only) and validated using RT-qPCR analysis. Our zebrafish sepsis model showed upregulation of dhcr7 and several of the same lipid genes upregulated in poor outcome human sepsis (dhcr24, sqlea, cyp51, msmo1 , ldlra) compared to controls. We then tested six lipid-based drugs in the zebrafish sepsis model. Of these, only the Dhcr7 inhibitor AY9944 completely rescued zebrafish from LPS death in a model with 100% lethality. Conclusions: DHCR7, an important cholesterol metabolism gene, was upregulated in poor outcome sepsis patients warranting external validation. This pathway may serve as a potential therapeutic target to improve sepsis outcomes.

Efficacy of Losartan in Hospitalized Patients With COVID-19-Induced Lung Injury: A Randomized Clinical Trial.

Importance: SARS-CoV-2 viral entry may disrupt angiotensin II (AII) homeostasis, contributing to COVID-19 induced lung injury. AII type 1 receptor blockade mitigates lung injury in preclinical models, although data in humans with COVID-19 remain mixed. Objective: To test the efficacy of losartan to reduce lung injury in hospitalized patients with COVID-19. Design, Setting, and Participants: This blinded, placebo-controlled randomized clinical trial was conducted in 13 hospitals in the United States from April 2020 to February 2021. Hospitalized patients with COVID-19 and a respiratory sequential organ failure assessment score of at least 1 and not already using a renin-angiotensin-aldosterone system (RAAS) inhibitor were eligible for participation. Data were analyzed from April 19 to August 24, 2021. Interventions: Losartan 50 mg orally twice daily vs equivalent placebo for 10 days or until hospital discharge. Main Outcomes and Measures: The primary outcome was the imputed arterial partial pressure of oxygen to fraction of inspired oxygen (Pao2:Fio2) ratio at 7 days. Secondary outcomes included ordinal COVID-19 severity; days without supplemental o2, ventilation, or vasopressors; and mortality. Losartan pharmacokinetics and RAAS components (AII, angiotensin-[1-7] and angiotensin-converting enzymes 1 and 2)] were measured in a subgroup of participants. Results: A total of 205 participants (mean [SD] age, 55.2 [15.7] years; 123 [60.0%] men) were randomized, with 101 participants assigned to losartan and 104 participants assigned to placebo. Compared with placebo, losartan did not significantly affect Pao2:Fio2 ratio at 7 days (difference, -24.8 [95%, -55.6 to 6.1]; P = .12). Compared with placebo, losartan did not improve any secondary clinical outcomes and led to fewer vasopressor-free days than placebo (median [IQR], 9.4 [9.1-9.8] vasopressor-free days vs 8.7 [8.2-9.3] vasopressor-free days). Conclusions and Relevance: This randomized clinical trial found that initiation of orally administered losartan to hospitalized patients with COVID-19 and acute lung injury did not improve Pao2:Fio2 ratio at 7 days. These data may have implications for ongoing clinical trials. Trial Registration: ClinicalTrials.gov Identifier: NCT04312009.

A hypolipoprotein sepsis phenotype indicates reduced lipoprotein antioxidant capacity, increased endothelial dysfunction and organ failure, and worse clinical outcomes.

OBJECTIVE: Approximately one-third of sepsis patients experience poor outcomes including chronic critical illness (CCI, intensive care unit (ICU) stay > 14 days) or early death (in-hospital death within 14 days). We sought to characterize lipoprotein predictive ability for poor outcomes and contribution to sepsis heterogeneity. DESIGN: Prospective cohort study with independent replication cohort. SETTING: Emergency department and surgical ICU at two hospitals. PATIENTS: Sepsis patients presenting within 24 h. METHODS: Measures included cholesterol levels (total cholesterol, high density lipoprotein cholesterol [HDL-C], low density lipoprotein cholesterol [LDL-C]), triglycerides, paraoxonase-1 (PON-1), and apolipoprotein A-I (Apo A-I) in the first 24 h. Inflammatory and endothelial markers, and sequential organ failure assessment (SOFA) scores were also measured. LASSO selection assessed predictive ability for outcomes. Unsupervised clustering was used to investigate the contribution of lipid variation to sepsis heterogeneity. MEASUREMENTS AND MAIN RESULTS: 172 patients were enrolled. Most (~ 67%, 114/172) rapidly recovered, while ~ 23% (41/172) developed CCI, and ~ 10% (17/172) had early death. ApoA-I, LDL-C, mechanical ventilation, vasopressor use, and Charlson Comorbidity Score were significant predictors of CCI/early death in LASSO models. Unsupervised clustering yielded two discernible phenotypes. The Hypolipoprotein phenotype was characterized by lower lipoprotein levels, increased endothelial dysfunction (ICAM-1), higher SOFA scores, and worse clinical outcomes (45% rapid recovery, 40% CCI, 16% early death; 28-day mortality, 21%). The Normolipoprotein cluster patients had higher cholesterol levels, less endothelial dysfunction, lower SOFA scores and better outcomes (79% rapid recovery, 15% CCI, 6% early death; 28-day mortality, 15%). Phenotypes were validated in an independent replication cohort (N = 86) with greater sepsis severity, which similarly demonstrated lower HDL-C, ApoA-I, and higher ICAM-1 in the Hypolipoprotein cluster and worse outcomes (46% rapid recovery, 23% CCI, 31% early death; 28-day mortality, 42%). Normolipoprotein patients in the replication cohort had better outcomes (55% rapid recovery, 32% CCI, 13% early death; 28-day mortality, 28%) Top features for cluster discrimination were HDL-C, ApoA-I, total SOFA score, total cholesterol level, and ICAM-1. CONCLUSIONS: Lipoproteins predicted poor sepsis outcomes. A Hypolipoprotein sepsis phenotype was identified and characterized by lower lipoprotein levels, increased endothelial dysfunction (ICAM-1) and organ failure, and worse clinical outcomes.

Lipid and lipoprotein predictors of functional outcomes and long-term mortality after surgical sepsis.

RATIONALE: Sepsis is a life-threatening, dysregulated response to infection. Lipid biomarkers including cholesterol are dynamically regulated during sepsis and predict short-term outcomes. In this study, we investigated the predictive ability of lipid biomarkers for physical function and long-term mortality after sepsis. METHODS: Prospective cohort study of sepsis patients admitted to a surgical intensive-care unit (ICU) within 24 h of sepsis bundle initiation. Samples were obtained at enrollment for lipid biomarkers. Multivariate regression models determined independent risk factors predictive of poor performance status (Zubrod score of 3/4/5) or survival at 1-year follow-up. MEASUREMENTS AND MAIN RESULTS: The study included 104 patients with surgical sepsis. Enrollment total cholesterol and high-density lipoprotein (HDL-C) levels were lower, and myeloperoxidase (MPO) levels were higher for patients with poor performance status at 1 year. A similar trend was seen in comparisons based on 1-year mortality, with HDL-C and ApoA-I levels being lower and MPO levels being higher in non-survivors. However, multivariable logistic regression only identified baseline Zubrod and initial SOFA score as significant independent predictors of poor performance status at 1 year. Multivariable Cox regression modeling for 1-year survival identified high Charlson comorbidity score, low ApoA-I levels, and longer vasopressor duration as predictors of mortality over 1-year post-sepsis. CONCLUSIONS: In this surgical sepsis study, lipoproteins were not found to predict poor performance status at 1 year. ApoA-I levels, Charlson comorbidity scores, and duration of vasopressor use predicted 1 year survival. These data implicate cholesterol and lipoproteins as contributors to the underlying pathobiology of sepsis.

Updates and controversies in the early management of sepsis and septic shock.

Sepsis is a common and life-threatening condition that requires early recognition and swift initial management. Diagnosis and treatment of sepsis and septic shock are fundamental for emergency clinicians, and include knowledge of clinical and laboratory indicators of subtle and overt organ dysfunction, infection source control, and protocols for prompt identification of the early signs of septic shock. This issue is a structured review of the literature on the management of sepsis, focusing on the current evidence, guidelines, and protocols.

Quantitative and Qualitative Assessments of Cholesterol Association With Bacterial Infection Type in Sepsis and Septic Shock.

BACKGROUND: Reduced cholesterol levels are associated with increased organ failure and mortality in sepsis. Cholesterol levels may vary by infection type (gram negative vs positive), possibly reflecting differences in cholesterol-mediated bacterial clearance. METHODS: This was a secondary analysis of a combined data set of 2 prospective cohort studies of adult patients meeting Sepsis-3 criteria. Infection types were classified as gram negative, gram positive, or culture negative. We investigated quantitative (levels) and qualitative (dysfunctional high-density lipoprotein [HDL]) cholesterol differences. We used multivariable logistic regression to control for disease severity. RESULTS: Among 171 patients with sepsis, infections were gram negative in 67, gram positive in 46, and culture negative in 47. Both gram-negative and gram-positive infections occurred in 11 patients. Total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and HDL cholesterol (HDL-C) levels were lower for culture-positive sepsis at enrollment (TC, P < .001; LDL-C, P < .001; HDL-C, P = .011) and persisted after controlling for disease severity. Similarly, cholesterol levels were lower among culture-positive patients at 48 hours (TC, P = .012; LDL-C, P = .029; HDL-C, P = .002). Triglyceride (TG) levels were lower at enrollment (P =.033) but not at 48 hours (P = .212). There were no differences in dysfunctional HDL. Among bacteremic patients, cholesterol levels were lower at enrollment (TC, P = .010; LDL-C, P = .010; HDL-C, P ≤ .001; TG, P = .005) and at 48 hours (LDL-C, P = .027; HDL-C, P < .001; TG, P = .020), except for 48 hour TC (P = .051). In the bacteremia subgroup, enrollment TC and LDL-C were lower for gram-negative versus gram-positive infections (TC, P = .039; LDL-C, P = .023). CONCLUSION: Cholesterol levels are significantly lower among patients with culture-positive sepsis and bacteremia.

Time to vasopressor initiation and organ failure progression in early septic shock.

OBJECTIVE: Research evaluating the relationship between vasopressor initiation timing and clinical outcomes is limited and conflicting. We investigated the association between time to vasopressors, worsening organ failure, and mortality in patients with septic shock. METHODS: This was a retrospective study of patients with septic shock (2013-2016) within 24 hours of emergency department (ED) presentation. The primary outcome was worsening organ failure, defined as an increase in Sequential Organ Failure Assessment (SOFA) score ≥2 at 48 hours compared to baseline, or death within 48 hours. The secondary outcome was 28-day mortality. Time to vasopressor initiation was categorized into 6, 4-hour intervals from time of ED triage. Multiple logistic regression was used to identify predictors of worsening organ failure. RESULTS: We analyzed data from 428 patients with septic shock. There were 152 patients with the composite primary outcome (SOFA increase ≥2 or death at 48 hours). Of these, 77 patients died in the first 48 hours and 75 patients had a SOFA increase ≥2. Compared to the patients who received vasopressors in the first 4 hours, those with the longest time to vasopressors (20-24 hours) had increased odds of developing worsening organ failure (odds ratios [OR] = 4.34, 95% confidence intervals [CI] = 1.47-12.79, P = 0.008). For all others, the association between vasopressor timing and worsening organ failure was non-significant. There was no association between time to vasopressor initiation and 28-day mortality. CONCLUSIONS: Increased time to vasopressor initiation is an independent predictor of worsening organ failure for patients with vasopressor initiation delays >20 hours.

Emergency Medicine Gender in Resident Leadership Study (EM GIRLS): The Gender Distribution Among Chief Residents.

OBJECTIVES: The goal of this research was to determine the gender distribution of chief residents in emergency medicine (EM) residencies in the United States to explore whether the gender leadership gap is present at the resident level in EM. METHODS: The investigators compiled a list of EM residency programs accredited by the Accreditation Council for Graduate Medical Education. Investigators reached out to the programs using established best practices in survey distribution collecting the following: program name, program location, program length, total number of residents, total number of female residents, total number of chief residents, and the total number of female chief residents. RESULTS: Of the 223 programs contacted 194 programs responded and 182 programs were included in the study (a response rate of 82%). As of the 2019 to 2020 academic year, female EM residents account for 37.0% (2,459/6,718) of all EM residents and female EM chief residents account for 42.2% (250/593) of EM chief residents. The proportion of female EM chief residents was significantly higher than the proportion of both female EM residents (42.2% vs. 37%, p = 0.007) and female EM attending physicians (42.2% vs. 27.5%, p < 0.001). When comparing proportions of female residents based on duration of program, female physicians comprised 35.0% (1,652/4,720) of residents at 3-year programs and 40.4% (807/1998) of residents at 4-year programs (p < 0.01). CONCLUSIONS: While the proportion of female EM residents remains significantly lower than the proportion of male residents, females and males are similarly represented at the chief resident role.

Lipid intensive drug therapy for sepsis pilot: A Bayesian phase I clinical trial.

OBJECTIVES: Cholesterol may be protective in sepsis. Patients with early sepsis may have critically low cholesterol levels that are associated with poor outcomes. The study objective was to test the safety of a fish oil-containing lipid injectable emulsion for stabilizing early cholesterol levels in sepsis. METHODS: Phase I Bayesian optimal interval design trial of adult patients with septic shock (Sequential Organ Failure Assessment score ≥4 or vasopressor dependence). Using sequential dose escalation, participants received 2 doses of 1.0 to 1.6 g/kg of lipid emulsion (Smoflipid 20% lipid emulsion) within 48 hours of enrollment. Cholesterol levels, function, and organ failure were assessed serially during the first 7 days of hospital admission. MEASUREMENTS AND MAIN RESULTS: A total of 10 patients with septic shock were enrolled. One patient withdrew for social reasons. Another patient had an unrelated medical complication and received 1 drug dose. Of 9 patients, mean age was 58 years (SD 16), median Sequential Organ Failure Assessment was 8, and 28-day mortality was 30%. No serious adverse events related to lipid infusion occurred. The six occurrences of non-serious adverse events possibly related to lipid infusion included hyperglycemia (1), elevated triglycerides (3), anemia (1), and vascular access redness/pain (1) for all doses. The mean change in total cholesterol levels from enrollment was -7 (SD 16.6) at 48 hours and 14 (SD 25.2) at 7 days. CONCLUSIONS: Fish oil-containing lipid emulsion administration during early septic shock was safe. Further studies are needed to assess effects on cholesterol levels, function, and organ failure. CLINICAL TRIAL REGISTRATION: NCT03405870.

LIPid Intensive Drug therapy for Sepsis Pilot (LIPIDS-P): Phase I/II clinical trial protocol of lipid emulsion therapy for stabilising cholesterol levels in sepsis and septic shock.

INTRODUCTION: Sepsis is a life-threatening, dysregulated response to infection. Both high-density lipoprotein and low-density lipoprotein cholesterol should protect against sepsis by several mechanisms; however, for partially unknown reasons, cholesterol levels become critically low in patients with early sepsis who experience poor outcomes. An anti-inflammatory lipid injectable emulsion containing fish oil is approved by the Food and Drug Administration as parenteral nutrition for critically ill patients and may prevent this decrease in serum cholesterol levels by providing substrate for cholesterol synthesis and may favourably modulate inflammation. This LIPid Intensive Drug therapy for Sepsis Pilot clinical trial is the first study to attempt to stabilise early cholesterol levels using lipid emulsion as a treatment modality for sepsis. METHODS AND ANALYSIS: This is a two-centre, phase I/II clinical trial. Phase I is a non-randomised dose-escalation study using a Bayesian optimal interval design in which up to 16 patients will be enrolled to evaluate the safest and most efficacious dose for stabilising cholesterol levels. Based on phase I results, the two best doses will be used to randomise 48 patients to either lipid injectable emulsion or active control (no treatment). Twenty-four patients will be randomised to one of two doses of the study drug, while 24 control group patients will receive no drug and will be followed during their hospitalisation. The control group will receive all standard treatments mandated by the institutional sepsis alert protocol. The phase II study will employ a permuted blocked randomisation technique, and the primary endpoint will be change in serum total cholesterol level (48 hours - enrolment). Secondary endpoints include change in cholesterol level from enrolment to 7 days, change in Sequential Organ Failure Assessment score over the first 48 hours and 7 days, in-hospital and 28-day mortality, lipid oxidation status, inflammatory biomarkers, and high-density lipoprotein function. ETHICS AND DISSEMINATION: Investigators are trained and follow good clinical practices, and each phase of the study was reviewed and approved by the institutional review boards of each institution. Results of each phase will be disseminated through presentations at national meetings and publication in peer-reviewed journals. If promising, data from the pilot study will be used for a larger, multicentre, phase II clinical trial. TRIAL REGISTRATION NUMBER: NCT03405870.

Points & Pearls: Updates and controversies in the early management of sepsis and septic shock

Sepsis is a common and life-threatening condition that requires early recognition and swift initial management. Diagnosis and treatment of sepsis and septic shock are fundamental for emergency clinicians, and include knowledge of clinical and laboratory indicators of subtle and overt organ dysfunction, infection source control, and protocols for prompt identification of the early signs of septic shock. [Points & Pearls is a digest of Emergency Medicine Practice.]

Updates and controversies in the early management of sepsis and septic shock.

Sepsis is a common and life-threatening condition that requires early recognition and swift initial management. Diagnosis and treatment of sepsis and septic shock are fundamental for emergency clinicians, and include knowledge of clinical and laboratory indicators of subtle and overt organ dysfunction, infection source control, and protocols for prompt identification of the early signs of septic shock. This issue is a structured review of the literature on the management of sepsis, focusing on the current evidence, guidelines, and protocols.

Limited course of antibiotic treatment for chorioamnionitis.

OBJECTIVE: We sought to estimate the effectiveness of a limited course of antibiotics in treating patients with chorioamnionitis. METHODS: We conducted a retrospective review of patients treated for chorioamnionitis at our medical center from 2005 to 2009. Patients received ampicillin plus gentamicin as soon as the diagnosis was made. Postpartum they received only the next scheduled dose of each antibiotic. Patients who underwent a cesarean delivery received either metronidazole or clindamycin immediately after cord clamping. The primary outcome was treatment failure, defined as persistent fever requiring continuation of antibiotics, surgical intervention, or administration of heparin. RESULTS: Of the 423 patients, 282 delivered vaginally, and 141 delivered by cesarean. Overall, 399 (94%; 95% confidence interval [CI], 92-96%) were treated successfully and 24 (6%; 95% CI 3.7-8.3%) failed short-course treatment. Of the 282 patients who delivered vaginally, 279 (99%; 95% CI 98-100%) were cured with short-term therapy. Of the 141 who delivered by cesarean, 120 (85%; 95% CI 79-91%) were cured (P<.001). Seventeen of the patients with total treatment failure had endometritis and responded to continuation of antibiotics. Seven patients had more serious complications: wound infection (n=4) and septic thrombophlebitis (n=3). All of the serious complications occurred after cesarean delivery, and all of the affected patients either were obese or had prolonged labor or prolonged rupture of membranes. CONCLUSION: A limited course of antibiotics was sufficient for virtually all patients (99%) with chorioamnionitis who had a vaginal delivery. However, a subset of patients who delivered by cesarean may have benefited from a more extended course of antibiotic therapy. LEVEL OF EVIDENCE: III.