Subgroup analysis of the lipid infusion and patient outcomes in sepsis trial (LIPOS) reveals benefit in a subgroup not treated with stress replacement doses of corticosteroids

Ts, Parker; Levine, DM; Gordon, BR; Saal, SD

doi:10.1186/cc14065

Cited by 7 publications

(10 citation statements)

References 3 publications

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“…Phillip Dellinger and colleagues41 performed a multicentre randomised controlled trial of a different drug (a phospholipid emulsion) for Gram-negative severe sepsis with the idea that the drug would be able to facilitate endotoxin clearance. Although the study initially demonstrated no effect on mortality,41 a secondary post-hoc analysis was performed that was limited to patients with albumin ≥1.5 g/dL and either total cholesterol ≥40 mg/dL or HDL-C ≥20 mg/dL and showed potential reduced mortality of 6.6% (p<0.025) and 10.8% (p<0.005), respectively 42. That study suggests that adequate liver function and a minimum quantity of circulating cholesterol are needed for effective lipid-mediated defence against sepsis, and guided the development of our inclusion/exclusion criteria.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2019

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IntroductionSepsis 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 analysisThis 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 disseminationInvestigators 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 numberNCT03405870.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2019

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“…The Lipid Infusion and Patient Outcomes in Sepsis (LIPOS) clinical trial used a phospholipid emulsion in gram-negative sepsis with the aim of clearing endotoxin and reducing 28-day mortality [ 156 ]. Results were negative, however, secondary analysis showed mortality benefit in patients with normal liver function and either total cholesterol >40 mg/dL or HDL >20 mg/dL [ 157 ]. Our group has previously shown in a phase I clinical trial, Lipid Intensive Drug therapy for Sepsis Pilot (LIPIDS-P) that omega-3 supplementation through a fish-oil containing lipid emulsion in early sepsis is safe, and promise toward stabilizing early total cholesterol and HDL levels [ 158 ].…”

Section: Lipid-based Therapiesmentioning

confidence: 99%

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

Barker

Leeuwenburgh

Brusko

et al. 2021

JCM

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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.

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“…30 Though this study found no differences in mortality between placebo, low-dose, and high-dose experimental drug groups, a secondary analysis in patients with a serum albumin ≥ 1.5 g/dL, and either a cholesterol ≥ 1mM or HDL ≥ 0.5 mM demonstrated reduced mortality in these subgroups by 6.6% (p < 0.025) and 10.8% (p< 0.005), respectively. 31 This post-hoc analysis also interestingly demonstrated a strong negative interaction between the study drug and intravenous corticosteroids, thought to be due to the ability of bile acids to slow clearance of the drug and raise corticosteroid concentrations. Overall, however, this study may be an unappreciated proof of concept study for lipid-based therapies for sepsis and demonstrates specifically, that in a septic patients with adequate liver function and a sufficient quantity of circulating HDL and total cholesterol, augmenting the process of reverse cholesterol transport may improve outcomes.…”

Section: Discussionmentioning

confidence: 74%

HDL Cholesterol Efflux is Impaired in Older Patients with Early Sepsis: A Subanalysis of a Prospective Pilot Study

Guirgis

Leeuwenburgh

Grijalva³

et al. 2018

Shock

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Subgroup analysis of the lipid infusion and patient outcomes in sepsis trial (LIPOS) reveals benefit in a subgroup not treated with stress replacement doses of corticosteroids

Cited by 7 publications

References 3 publications

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

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

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

HDL Cholesterol Efflux is Impaired in Older Patients with Early Sepsis: A Subanalysis of a Prospective Pilot Study

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