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.

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.

Racial disparities in septic shock mortality: a retrospective cohort study.

Background: Patients with septic shock have the highest risk of death from sepsis, however, racial disparities in mortality outcomes in this cohort have not been rigorously investigated. Our objective was to describe the association between race/ethnicity and mortality in patients with septic shock. Methods: Our study is a retrospective cohort study of adult patients in the OneFlorida Data Trust (Florida, United States of America) admitted with septic shock between January 2012 and July 2018. We identified patients as having septic shock if they received vasopressors during their hospital encounter and had either an explicit International Classification of Disease (ICD) code for sepsis, or had an infection ICD code and received intravenous antibiotics. Our primary outcome was 90-day mortality. Our secondary outcome was in-hospital mortality. Multiple logistic regression with Least Absolute Shrinkage and Selection Operator (LASSO) for variable selection was used to assess associations. Findings: There were 13,932 patients with septic shock in our cohort. The mean age was 61 years (SD 16), 68% of the cohort identified as White (n = 9419), 28% identified as Black (n = 3936), 2% (n = 294) identified as Hispanic ethnicity, and 2% as other races not specified in the previous groups (n = 283). In our logistic regression model for 90-day mortality, patients identified as Black had 1.57 times the odds of mortality (95% CI 1.07-2.29, p = 0.02) compared to White patients. Other significant predictors included mechanical ventilation (OR 3.66, 95% CI 3.35-4.00, p < 0.01), liver disease (OR 1.75, 95% CI 1.59-1.93, p < 0.01), laboratory components of the Sequential Organ Failure Assessment score (OR 1.18, 95% CI 1.16-1.21, p < 0.01), lactate (OR 1.10, 95% CI 1.08-1.12, p < 0.01), congestive heart failure (OR 1.19, 95% CI 1.10-1.30, p < 0.01), human immunodeficiency virus (OR 1.35, 95% CI 1.04-1.75, p = 0.03), age (OR 1.04, 95% CI 1.04-1.04, p < 0.01), and the interaction between age and race (OR 0.99, 95% CI 0.99-1.00, p < 0.01). Among younger patients (<45 years), patients identified as Black accounted for a higher proportion of the deaths. Results were similar in the in-hospital mortality model. Interpretation: In this retrospective study of septic shock patients, we found that patients identified as Black had higher odds of mortality compared to patients identified as non-Hispanic White. Our findings suggest that the greatest disparities in mortality are among younger Black patients with septic shock. Funding: National Institutes of Health National Center for Advancing Translational Sciences (1KL2TR001429); National Institute of Health National Institute of General Medical Sciences (1K23GM144802).

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.

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.

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.

Association Between Hypocholesterolemia and Mortality in Critically Ill Patients With Sepsis: A Systematic Review and Meta-Analysis.

To ascertain the association between cholesterol and triglyceride levels on ICU admission and mortality in patients with sepsis. DATA SOURCES: Systematic review and meta-analysis of published studies on PubMed and Embase. STUDY SELECTION: All observational studies reporting ICU admission cholesterol and triglyceride levels in critically ill patients with sepsis were included. Authors were contacted for further data. DATA EXTRACTION: Eighteen observational studies were identified, including 1,283 patients with a crude overall mortality of 33.3%. Data were assessed using Revman (Version 5.1, Cochrane Collaboration, Oxford, United Kingdom) and presented as mean difference (MD) with 95% CIs, p values, and I 2 values. DATA SYNTHESIS: Admission levels of total cholesterol (17 studies, 1,204 patients; MD = 0.52 mmol/L [0.27-0.77 mmol/L]; p < 0.001; I 2 = 91%), high-density lipoprotein (HDL)-cholesterol (14 studies, 991 patients; MD = 0.08 mmol/L [0.01-0.15 mmol/L]; p = 0.02; I 2 = 61%), and low-density lipoprotein (LDL)-cholesterol (15 studies, 1,017 patients; MD = 0.18 mmol/L [0.04-0.32 mmol/L]; p = 0.01; I 2 = 71%) were significantly lower in eventual nonsurvivors compared with survivors. No association was seen between admission triglyceride levels and mortality (15 studies, 1,070 patients; MD = 0.00 mmol/L [-0.16 to 0.15 mmol/L]; p = -0.95; I 2 = 79%). CONCLUSIONS: Mortality was associated with lower levels of total cholesterol, HDL-cholesterol, and LDL-cholesterol, but not triglyceride levels, in patients admitted to ICU with sepsis. The impact of cholesterol replacement on patient outcomes in sepsis, particularly in at-risk groups, merits investigation.

Overtriage, Undertriage, and Value of Care after Major Surgery: An Automated, Explainable Deep Learning-Enabled Classification System.

BACKGROUND: In single-institution studies, overtriaging low-risk postoperative patients to ICUs has been associated with a low value of care; undertriaging high-risk postoperative patients to general wards has been associated with increased mortality and morbidity. This study tested the reproducibility of an automated postoperative triage classification system to generating an actionable, explainable decision support system. STUDY DESIGN: This longitudinal cohort study included adults undergoing inpatient surgery at two university hospitals. Triage classifications were generated by an explainable deep learning model using preoperative and intraoperative electronic health record features. Nearest neighbor algorithms identified risk-matched controls. Primary outcomes were mortality, morbidity, and value of care (inverted risk-adjusted mortality/total direct costs). RESULTS: Among 4,669 ICU admissions, 237 (5.1%) were overtriaged. Compared with 1,021 control ward admissions, overtriaged admissions had similar outcomes but higher costs ($15.9K [interquartile range $9.8K to $22.3K] vs $10.7K [$7.0K to $17.6K], p < 0.001) and lower value of care (0.2 [0.1 to 0.3] vs 1.5 [0.9 to 2.2], p < 0.001). Among 8,594 ward admissions, 1,029 (12.0%) were undertriaged. Compared with 2,498 control ICU admissions, undertriaged admissions had longer hospital length-of-stays (6.4 [3.4 to 12.4] vs 5.4 [2.6 to 10.4] days, p < 0.001); greater incidence of hospital mortality (1.7% vs 0.7%, p = 0.03), cardiac arrest (1.4% vs 0.5%, p = 0.04), and persistent acute kidney injury without renal recovery (5.2% vs 2.8%, p = 0.002); similar costs ($21.8K [$13.3K to $34.9K] vs $21.9K [$13.1K to $36.3K]); and lower value of care (0.8 [0.5 to 1.3] vs 1.2 [0.7 to 2.0], p < 0.001). CONCLUSIONS: Overtriage was associated with low value of care; undertriage was associated with both low value of care and increased mortality and morbidity. The proposed framework for generating automated postoperative triage classifications is reproducible.

Clinical predictors of endotracheal intubation in patients presenting to the emergency department with angioedema.

OBJECTIVES: The objective of this study is to identify predictors of airway compromise among patients presenting to the emergency department with angioedema in order to develop and validate a risk score to augment clinician gestalt regarding need for intubation. METHODS: Retrospective chart review of emergency department patients with a diagnosis of angioedema. After data extraction they were randomly divided into a training and test set. The training set was used to identify factors associated with intubation and to develop a model and risk score to predict intubation. The model and risk score were then applied to the test set. RESULTS: A total of 594 patients were included. Past medical history of hypertension, presence of shortness of breath, drooling, and anterior tongue or pharyngeal swelling were independent predictors included in our final model and risk score. The Area Under the Curve for the Receiver Operator Characteristic curve was 87.55% (83.42%-91.69%) for the training set and 86.1% (77.62%-94.60%) for the test set. CONCLUSIONS: A simple scoring algorithm may aid in predicting angioedema patients at high and low risk for intubation. External validation of this score is necessary before wide-spread adoption of this decision aid.

Differential Peripheral Blood Glycoprotein Profiles in Symptomatic and Asymptomatic COVID-19.

Glycosylation is the most common form of post-translational modification of proteins, critically affecting their structure and function. Using liquid chromatography and mass spectrometry for high-resolution site-specific quantification of glycopeptides coupled with high-throughput artificial intelligence-powered data processing, we analyzed differential protein glycoisoform distributions of 597 abundant serum glycopeptides and nonglycosylated peptides in 50 individuals who had been seriously ill with COVID-19 and in 22 individuals who had recovered after an asymptomatic course of COVID-19. As additional comparison reference phenotypes, we included 12 individuals with a history of infection with a common cold coronavirus, 16 patients with bacterial sepsis, and 15 healthy subjects without history of coronavirus exposure. We found statistically significant differences, at FDR < 0.05, for normalized abundances of 374 of the 597 peptides and glycopeptides interrogated between symptomatic and asymptomatic COVID-19 patients. Similar statistically significant differences were seen when comparing symptomatic COVID-19 patients to healthy controls (350 differentially abundant peptides and glycopeptides) and common cold coronavirus seropositive subjects (353 differentially abundant peptides and glycopeptides). Among healthy controls and sepsis patients, 326 peptides and glycopeptides were found to be differentially abundant, of which 277 overlapped with biomarkers that showed differential expression between symptomatic COVID-19 cases and healthy controls. Among symptomatic COVID-19 cases and sepsis patients, 101 glycopeptide and peptide biomarkers were found to be statistically significantly abundant. Using both supervised and unsupervised machine learning techniques, we found specific glycoprotein profiles to be strongly predictive of symptomatic COVID-19 infection. LASSO-regularized multivariable logistic regression and K-means clustering yielded accuracies of 100% in an independent test set and of 96% overall, respectively. Our findings are consistent with the interpretation that a majority of glycoprotein modifications observed which are shared among symptomatic COVID-19 and sepsis patients likely represent a generic consequence of a severe systemic immune and inflammatory state. However, there are glycoisoform changes that are specific and particular to severe COVID-19 infection. These may be representative of either COVID-19-specific consequences or susceptibility to or predisposition for a severe course of the disease. Our findings support the potential value of glycoproteomic biomarkers in the biomedical understanding and, potentially, the clinical management of serious acute infectious conditions.

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.

HDL and persistent inflammation immunosuppression and catabolism syndrome.

PURPOSE OF REVIEW: This study reviews the mechanisms of HDL cholesterol immunomodulation in the context of the mechanisms of chronic inflammation and immunosuppression causing persistent inflammation, immunosuppression and catabolism syndrome (PICS) and describes potential therapies and gaps in current research. RECENT FINDINGS: Low HDL cholesterol is predictive of acute sepsis severity and outcome. Recent research has indicated apolipoprotein is a prognostic indicator of long-term outcomes. The pathobiologic mechanisms of PICS have been elucidated in the past several years. Recent research of the interaction of HDL pathways in related chronic inflammatory diseases may provide insights into further mechanisms and therapeutic targets. SUMMARY: HDL significantly influences innate and adaptive immune pathways relating to chronic disease and inflammation. Further research is needed to better characterize these interactions in the setting of PICS.

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.

Most emergency department patients meeting sepsis criteria are not diagnosed with sepsis at discharge.

OBJECTIVES: Effective sepsis resuscitation depends on useful criteria for prompt identification of eligible patients. These criteria should reliably predict a discharge diagnosis of sepsis, ensuring that interventions are triggered for those who need it while avoiding potentially harmful interventions in those who do not. We sought to determine the proportion of patients meeting sepsis criteria in the emergency department (ED) that was ultimately diagnosed with sepsis and to quantify the subset of nonseptic patients with risk factors for harm from fluid resuscitation. METHODS: This retrospective cohort study of adult ED patients at a tertiary academic medical center included vital signs and laboratory results from the first 6 hours, plus administration of intravenous antibiotics, to determine if patients met 2016 Sepsis-3 consensus criteria. If these patients also had hypotension and lactic acidosis, we categorized them as Sepsis-3 plus shock. We used discharge ICD-9 codes to determine if patients were ultimately diagnosed with sepsis. RESULTS: Over 8 years, 3,121 ED patients met 2016 Sepsis-3 criteria in the first 6 hours. Of these, only 25% and 48% met explicit and implicit criteria for a discharge diagnosis of sepsis. Of 1,032 patients with Sepsis-3 plus shock, 48% and 62% met explicit and implicit criteria. Overall, 60% to 75% of ED patients meeting Sepsis-3 criteria with or without shock did not receive a sepsis discharge diagnosis. At least one plausible risk factor for harm from large-volume fluid resuscitation was identified among 19% to 36% of patients meeting sepsis criteria in the ED but not ultimately diagnosed with sepsis at discharge. CONCLUSIONS: Most patients meeting sepsis criteria in the ED were not diagnosed with sepsis at discharge. Urgent treatment bundles triggered by consensus criteria in the early phase of ED care may be administered to several patients without sepsis, potentially exposing some to interventions of uncertain benefit and possible harm.

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.

Lipid and Lipoprotein Dysregulation in Sepsis: Clinical and Mechanistic Insights into Chronic Critical Illness.

In addition to their well-characterized roles in metabolism, lipids and lipoproteins have pleiotropic effects on the innate immune system. These undergo clinically relevant alterations during sepsis and acute inflammatory responses. High-density lipoprotein (HDL) plays an important role in regulating the immune response by clearing bacterial toxins, supporting corticosteroid release, decreasing platelet aggregation, inhibiting endothelial cell apoptosis, reducing the monocyte inflammatory response, and inhibiting expression of endothelial cell adhesion molecules. It undergoes quantitative as well as qualitative changes which can be measured using the HDL inflammatory index (HII). Pro-inflammatory, or dysfunctional HDL (dysHDL) lacks the ability to perform these functions, and we have also found it to independently predict adverse outcomes and organ failure in sepsis. Another important class of lipids known as specialized pro-resolving mediators (SPMs) positively affect the escalation and resolution of inflammation in a temporal fashion. These undergo phenotypic changes in sepsis and differ significantly between survivors and non-survivors. Certain subsets of sepsis survivors go on to have perilous post-hospitalization courses where this inflammation continues in a low grade fashion. This is associated with immunosuppression in a syndrome of persistent inflammation, immunosuppression, and catabolism syndrome (PICS). The continuous release of tissue damage-related patterns and viral reactivation secondary to immunosuppression feed this chronic cycle of inflammation. Animal data indicate that dysregulation of endogenous lipids and SPMs play important roles in this process. Lipids and their associated pathways have been the target of many clinical trials in recent years which have not shown mortality benefit. These results are limited by patient heterogeneity and poor animal models. Considerations of sepsis phenotypes and novel biomarkers in future trials are important factors to be considered in future research. Further characterization of lipid dysregulation and chronic inflammation during sepsis will aid mortality risk stratification, detection of sepsis, and inform individualized pharmacologic therapies.

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.