Efficacy and safety of a phospholipid emulsion (GR270773) in Gram-negative severe sepsis: Results of a phase II multicenter, randomized, placebo-controlled, dose-finding clinical trial

Dellinger, R. Phillip; Tomayko, John F.; Angus, Derek C.; Opal, Steven M.; Cupo, Michael; McDermott, Sharon; Ducher, Annie; Calandra, Thierry; Cohen, Jonathan B.

doi:10.1097/ccm.0b013e3181b0266c

Cited by 59 publications

(31 citation statements)

References 25 publications

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“…Generally speaking, endotoxin is present in many critically ill patients without the criteria of sepsis [3]. To date, studies neutralizing the effects of endotoxin activity have not shown any benefit, the latest being the phospholipid study [21] and the inhibitor of Toll-like receptor-4-mediated signaling study [22]. It may well be that total neutralization of endotoxin is deleterious.…”

Section: Discussionmentioning

confidence: 99%

A New Endotoxin Adsorber in Septic Shock: Observational Case Series

2011

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Aims: Effects of a new endotoxin adsorber on the length of noradrenaline (NA) treatment, LPS (lipopolysaccharide) levels and SOFA (sequential organ failure assessment) scores in septic shock were evaluated. Methods: Two-hour hemoperfusion with LPS adsorber was initiated in patients with septic shock and endotoxemia. Controls were matched for age, focus and severity of illness. Results: Adsorption treatment (n = 9) exhibited a significant decrease in EAA (endotoxin activity assay) activity (0.55 [0.44–0.68] vs. 0.25 [0.13–0.41], p = 0.019) and NA infusion rate (0.217 µg/kg/min [0.119–0.0508] vs. 0 µg/kg/min [0–0.09], p = 0.026) from pretreatment to 24 h post-treatment. The median decrease in SOFA scores from pretreatment to 24 h was 3.0 points (1.5–4.5), p = 0.002. Duration of NA infusion was significantly shorter compared to controls (39 h [31–48] vs. 54 h [43–151], p = 0.03). Conclusions: LPS adsorber treatment was associated with a decrease in NA dose, decrease in SOFA scores and LPS concentrations.

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Section: Discussionmentioning

confidence: 99%

A New Endotoxin Adsorber in Septic Shock: Observational Case Series

2011

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“…However, several large follow-up randomized controlled trials with both HA-1A as well as E5 were negative and neither drug was approved for clinical use in the United States [12,13]. More recently, additional attempts at neutralizing endotoxin to increase survival in severe sepsis utilizing (a) bactericidal/permeability-increasing protein, (b) a lipid emulsion of recombinant HDL that binds endotoxin, (c) a small molecule TLR4 inhibitor (TAK242), and (d) E5564, a lipid A analogue and competitive inhibitor of TLR4, also all failed to show reduction in mortality in severe sepsis patients [14-16]. …”

Section: Introductionmentioning

confidence: 99%

The EUPHRATES trial (Evaluating the Use of Polymyxin B Hemoperfusion in a Randomized controlled trial of Adults Treated for Endotoxemia and Septic shock): study protocol for a randomized controlled trial

Klein

Foster²,

Schorr

et al. 2014

Trials

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BackgroundSeptic shock is common and has unacceptably high morbidity, mortality, and associated cost with numerous failed attempts at developing effective therapies. Endotoxin, one of the most potent mediators of sepsis, is found in high levels in approximately 50% of patients with septic shock. Polymyxin B (PMX) hemoperfusion has been shown in numerous studies to successfully remove endotoxin and potentially improve outcomes. EUPHRATES (Evaluating the Use of Polymyxin B Hemoperfusion in a Randomized controlled trial of Adults Treated for Endotoxemia and Septic shock) is a theragnostic trial (matching blood measurement to treatment capability) of PMX hemoperfusion in patients with septic shock and confirmed endotoxemia as measured by the endotoxin activity assay (EAA).MethodsEUPHRATES is a pivotal regulatory trial that is multi-centered, placebo-controlled and blinded. The trial is being conducted in fifty ICUs in the United States and Canada and is powered to enroll 360 patients. Patients with persistent septic shock despite adequate fluid resuscitation on vasopressors for more than 2 and less than 30 hours are eligible for measurement of the EAA. Those with EAA ≥0.60 are eligible to be randomized to treatment with two sessions of PMX hemoperfusion 24 hours apart. The primary endpoint for the trial is 28-day all-cause mortality.DiscussionUnique features of the trial include absence of systemic inflammatory response (SIRS) criteria as a requirement for inclusion, use of the EAA to confirm endotoxemia as a requisite for treatment, and use of a detailed “façade” hemoperfusion event as a blinding mechanism. The outcomes of the second interim analysis included a resizing of the trial to 650 patients and the addition of an exclusion criterion of subjects with multiple organ dysfunction score (MODS) ≤ 9. Results are anticipated in 2016.Trial registrationClinicaltrials.gov identifier: NCT01046669. Registered: January 8, 2010.

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“…This effect has been shown previously in a study of normal human volunteers receiving an intravenous dose of Escherichia coli endotoxin during a 6-h PL infusion, and attenuation of the clinical and laboratory responses were directly related to PL levels in the bloodstream [39]. However, when this formulation was tested in the critical care setting in patients with severe Gram-negative sepsis, the high dose arm (1350 mg/kg by continuous infusion) had to be stopped because of the increased incidence of life-threatening significant adverse events and obvious futilty to show a survival advantage [40]. The PL emulsion used in this investigation consisted of 92.5% soy-based, PL, and 7.5% soy triglycerides.…”

Section: Discussionmentioning

confidence: 99%

Krill Oil-In-Water Emulsion Protects against Lipopolysaccharide-Induced Proinflammatory Activation of Macrophages In Vitro

et al. 2017

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Background: Parenteral nutrition is often a mandatory therapeutic strategy for cases of septicemia. Likewise, therapeutic application of anti-oxidants, anti-inflammatory therapy, and endotoxin lowering, by removal or inactivation, might be beneficial to ameliorate the systemic inflammatory response during the acute phases of critical illness. Concerning anti-inflammatory properties in this setting, omega-3 fatty acids of marine origin have been frequently described. This study investigated the anti-inflammatory and LPS-inactivating properties of krill oil (KO)-in-water emulsion in human macrophages in vitro. Materials and Methods: Differentiated THP-1 macrophages were activated using specific ultrapure-LPS that binds only on the toll-like receptor 4 (TLR4) in order to determine the inhibitory properties of the KO emulsion on the LPS-binding capacity, and the subsequent release of TNF-α. Results: KO emulsion inhibited the macrophage binding of LPS to the TLR4 by 50% (at 12.5 µg/mL) and 75% (at 25 µg/mL), whereas, at 50 µg/mL, completely abolished the LPS binding. Moreover, KO (12.5 µg/mL, 25 µg/mL, or 50 µg/mL) also inhibited (30%, 40%, or 75%, respectively) the TNF-α release after activation with 0.01 µg/mL LPS in comparison with LPS treatment alone. Conclusion: KO emulsion influences the LPS-induced pro-inflammatory activation of macrophages, possibly due to inactivation of the LPS binding capacity.

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Efficacy and safety of a phospholipid emulsion (GR270773) in Gram-negative severe sepsis: Results of a phase II multicenter, randomized, placebo-controlled, dose-finding clinical trial

Abstract: Treatment with phospholipid emulsion did not reduce 28-day all-cause mortality, or reduce the onset of new organ failure in patients with suspected or confirmed Gram-negative severe sepsis.

Cited by 59 publications

References 25 publications

A New Endotoxin Adsorber in Septic Shock: Observational Case Series

A New Endotoxin Adsorber in Septic Shock: Observational Case Series

The EUPHRATES trial (Evaluating the Use of Polymyxin B Hemoperfusion in a Randomized controlled trial of Adults Treated for Endotoxemia and Septic shock): study protocol for a randomized controlled trial

Krill Oil-In-Water Emulsion Protects against Lipopolysaccharide-Induced Proinflammatory Activation of Macrophages In Vitro

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