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

Sulaiman, Dawoud / Wu, Dongyuan / Black, Lauren Page / Williams, Kevin J / Graim, Kiley / Datta, Susmita / Reddy, Srinivasa T / Guirgis, Faheem W

Clinical and translational science

2024 Volume 17, Issue 3, Page(s) e13745

Abstract: 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 ... ...

Abstract	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.
MeSH term(s)	Adult ; Humans ; Lipidomics ; Fatty Acids, Omega-3 ; Sepsis ; Fatty Acids ; Mass Spectrometry
Chemical Substances	Fatty Acids, Omega-3 ; Fatty Acids
Language	English
Publishing date	2024-03-15
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2433157-0
ISSN	1752-8062 ; 1752-8054
ISSN (online)	1752-8062
ISSN	1752-8054
DOI	10.1111/cts.13745
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: HDL and persistent inflammation immunosuppression and catabolism syndrome.

Barker, Grant / Winer, Julia R / Guirgis, Faheem W / Reddy, Srinivasa

Current opinion in lipidology

2021 Volume 32, Issue 5, Page(s) 315–322

Abstract: 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 ...

Abstract	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.
MeSH term(s)	Critical Illness ; Humans ; Immune Tolerance ; Immunosuppression Therapy ; Inflammation/metabolism ; Syndrome
Language	English
Publishing date	2021-08-06
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	1045394-5
ISSN	1473-6535 ; 0957-9672
ISSN (online)	1473-6535
ISSN	0957-9672
DOI	10.1097/MOL.0000000000000782
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Article ; Online: Association Between Hypocholesterolemia and Mortality in Critically Ill Patients With Sepsis: A Systematic Review and Meta-Analysis.

Hofmaenner, Daniel A / Arina, Pietro / Kleyman, Anna / Page Black, Lauren / Salomao, Reinaldo / Tanaka, Sébastien / Guirgis, Faheem W / Arulkumaran, Nishkantha / Singer, Mervyn

Critical care explorations

2023 Volume 5, Issue 2, Page(s) e0860

Abstract: 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 ... ...

Abstract	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, Data synthesis: Admission levels of total cholesterol (17 studies, 1,204 patients; MD = 0.52 mmol/L [0.27-0.77 mmol/L]; 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.
Language	English
Publishing date	2023-02-01
Publishing country	United States
Document type	Journal Article ; Review
ISSN	2639-8028
ISSN (online)	2639-8028
DOI	10.1097/CCE.0000000000000860
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Article ; Online: Response to the Letter: "Bias estimation of predictors and internal validity of the study 'Admission characteristics predictive of in-hospital death from hospital-acquired sepsis: A comparison to community-acquired sepsis'".

Gautam, Shiva / Smotherman, Carmen / Guirgis, Faheem W

Journal of critical care

2019 Volume 56, Page(s) 322

MeSH term(s)	Hospital Mortality ; Hospitalization ; Humans ; Sepsis
Language	English
Publishing date	2019-04-26
Publishing country	United States
Document type	Letter ; Comment
ZDB-ID	632818-0
ISSN	1557-8615 ; 0883-9441
ISSN (online)	1557-8615
ISSN	0883-9441
DOI	10.1016/j.jcrc.2019.04.023
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Article ; Online: The Lipid Intensive Drug Therapy for Sepsis Phase II Pilot Clinical Trial.

Guirgis, Faheem W / Black, Lauren Page / Henson, Morgan / Bertrand, Andrew / DeVos, Elizabeth / Ferreira, Jason / Gao, Hanzhi / Wu, Samuel S / Leeuwenburgh, Christiaan / Moldawer, Lyle / Moore, Frederick / Reddy, Srinivasa T

Critical care medicine

2024

Abstract: 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 ... ...

Abstract	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.
Language	English
Publishing date	2024-03-15
Publishing country	United States
Document type	Journal Article
ZDB-ID	197890-1
ISSN	1530-0293 ; 0090-3493
ISSN (online)	1530-0293
ISSN	0090-3493
DOI	10.1097/CCM.0000000000006268
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Article: Lipid and Lipoprotein Dysregulation in Sepsis: Clinical and Mechanistic Insights into Chronic Critical Illness.

Barker, Grant / Leeuwenburgh, Christiaan / Brusko, Todd / Moldawer, Lyle / Reddy, Srinivasa T / Guirgis, Faheem W

Journal of clinical medicine

2021 Volume 10, Issue 8

Abstract: 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 ... ...

Abstract	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.
Language	English
Publishing date	2021-04-14
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2662592-1
ISSN	2077-0383
ISSN	2077-0383
DOI	10.3390/jcm10081693
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Article ; Online: Racial disparities in septic shock mortality: a retrospective cohort study.

Black, Lauren P / Hopson, Charlotte / Puskarich, Michael A / Modave, Francois / Booker, Staja Q / DeVos, Elizabeth / Fernandez, Rosemarie / Garvan, Cynthia / Guirgis, Faheem W

Lancet regional health. Americas

2023 Volume 29, Page(s) 100646

Abstract: 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/ ... ...

Abstract	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 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).
Language	English
Publishing date	2023-12-12
Publishing country	England
Document type	Journal Article
ISSN	2667-193X
ISSN (online)	2667-193X
DOI	10.1016/j.lana.2023.100646
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Article ; Online: Time to vasopressor initiation and organ failure progression in early septic shock.

Black, Lauren Page / Puskarich, Michael A / Smotherman, Carmen / Miller, Taylor / Fernandez, Rosemarie / Guirgis, Faheem W

Journal of the American College of Emergency Physicians open

2020 Volume 1, Issue 3, Page(s) 222–230

Abstract: 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 ...

Abstract	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, Conclusions: Increased time to vasopressor initiation is an independent predictor of worsening organ failure for patients with vasopressor initiation delays >20 hours.
Language	English
Publishing date	2020-05-02
Publishing country	United States
Document type	Journal Article
ISSN	2688-1152
ISSN (online)	2688-1152
DOI	10.1002/emp2.12060
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Article ; Online: TRENDS IN CHOLESTEROL AND LIPOPROTEINS ARE ASSOCIATED WITH ACUTE RESPIRATORY DISTRESS SYNDROME INCIDENCE AND DEATH AMONG SEPSIS PATIENTS.

Black, Lauren Page / Hopson, Charlotte / Barker, Grant / Munson, Taylor / Henson, Morgan / Bertrand, Andrew / Daly-Crews, Kimberly / Reddy, Srinivasa T / Guirgis, Faheem W

Shock (Augusta, Ga.)

2023 Volume 61, Issue 2, Page(s) 260–265

Abstract: 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. ... ...

Abstract	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.
MeSH term(s)	Humans ; Cholesterol, LDL ; Apolipoprotein A-I ; Incidence ; Prospective Studies ; Cholesterol ; Sepsis/complications ; Lipoproteins ; Respiratory Distress Syndrome
Chemical Substances	Cholesterol, LDL ; Apolipoprotein A-I ; Cholesterol (97C5T2UQ7J) ; Lipoproteins
Language	English
Publishing date	2023-12-28
Publishing country	United States
Document type	Journal Article
ZDB-ID	1185432-7
ISSN	1540-0514 ; 1073-2322
ISSN (online)	1540-0514
ISSN	1073-2322
DOI	10.1097/SHK.0000000000002295
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Article ; Online: Admission characteristics predictive of in-hospital death from hospital-acquired sepsis: A comparison to community-acquired sepsis.

Padro, Teresa / Smotherman, Carmen / Gautam, Shiva / Gerdik, Cynthia / Gray-Eurom, Kelly / Guirgis, Faheem W

Journal of critical care

2019 Volume 51, Page(s) 145–148

Abstract: Purpose: Healthcare associated (HA) sepsis is associated with increased resource utilization and mortality compared with community acquired (CA) sepsis. The purpose of this study was to identify independent predictors of in-hospital mortality from HA- ... ...

Abstract	Purpose: Healthcare associated (HA) sepsis is associated with increased resource utilization and mortality compared with community acquired (CA) sepsis. The purpose of this study was to identify independent predictors of in-hospital mortality from HA-sepsis. Materials and methods: Retrospective study of adult patients admitted with HA or CA-sepsis. Predictors were identified using logistic regression. Results: There were 3917 sepsis encounters, of which 3186 were CA and 731 were HA. History of stroke (83/731, 11%) and myocardial infarction (70/731, 10%) were higher in HA than CA-sepsis (stroke: 258/3186, 8%, p = .005; myocardial infarction: 213/3186, 7%, p = .007). HA-sepsis patients required more mechanical ventilation (153/731, 21%) than CA-patients (218/3186, 7%, p < .001) and had a higher rate of vasopressor use (334/731, 46%) than CA patients (832/3186, 26%, p < .001). The HA group had longer ICU lengths of stay (LOS) than CA patients did at 9 days and 2.8 days, respectively (p < .0001). Moderate to severe liver disease (OR = 27, 95%CI 1.4, 513, p = .031) and congestive heart failure (CHF, 5.81, 95% CI 1.3, 26, p = .025) were predictive of in-hospital mortality from HA-sepsis. Conclusions: Liver disease and CHF were independent predictors of in-hospital mortality in HA-sepsis. HA-sepsis patients had increased prevalence of previous stroke, myocardial infarction, and liver disease.
MeSH term(s)	Adult ; Aged ; Female ; Heart Failure/complications ; Hospital Mortality ; Hospitalization/statistics & numerical data ; Humans ; Length of Stay/statistics & numerical data ; Liver Diseases/complications ; Logistic Models ; Male ; Middle Aged ; Predictive Value of Tests ; Prevalence ; Retrospective Studies ; Sepsis/mortality
Language	English
Publishing date	2019-02-19
Publishing country	United States
Document type	Journal Article
ZDB-ID	632818-0
ISSN	1557-8615 ; 0883-9441
ISSN (online)	1557-8615
ISSN	0883-9441
DOI	10.1016/j.jcrc.2019.02.023
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