Intravenous omega-3 fatty acids are associated with better clinical outcome and less inflammation in patients with predicted severe acute pancreatitis: A randomised double blind controlled trial.

BACKGROUND AND AIMS: Omega-3 fatty acids (FA) can ameliorate the hyper-inflammatory response that occurs in conditions such as severe acute pancreatitis (SAP) and this may improve clinical outcome. We tested the hypothesis that parenteral omega-3 FA from a lipid emulsion that includes fish oil could be beneficial in patients with predicted SAP by reducing C-reactive protein (CRP) concentration (primary outcome), and modulating the inflammatory response and improving clinical outcome (secondary outcomes). METHODS: In a phase II randomized double-blind single-centre controlled trial, patients with predicted SAP were randomised to receive a daily infusion of fish oil containing lipid emulsion (Lipidem® 20%, BBraun) for 7 days (n = 23) or a daily infusion of a lipid emulsion without fish oil (Lipofundin® MCT 20%, BBraun) (n = 22). RESULTS: On admission, both groups had comparable pancreatitis predicted severity and APACHE II scores. Administration of fish oil resulted in lower total blood leukocyte number (P = 0.04), CRP (P = 0.013), interleukin-8 (P = 0.05) and intercellular adhesion molecule 1 (P = 0.01) concentrations, multiple organ dysfunction score, sequential organ failure assessment score (P = 0.004), early warning score (P = 0.01), and systemic inflammatory response syndrome (P = 0.03) compared to the control group. The fish oil group had fewer new organ failures (P = 0.07), lower critical care admission rate (P = 0.06), shorter critical care stay (P = 0.03) and shorter total hospital stay (P = 0.04). CONCLUSIONS: It is concluded that intravenous administration of a fish oil containing lipid emulsion, a source of omega-3 FA, improves clinical outcomes in patients with predicted SAP, benefits that may be linked to reduced inflammation. CLINICALTRIALS. GOV NUMBER: NCT01745861. EU CLINICAL TRIALS REGISTER: EudraCT (2010-018660-16).

Cellular and plasma uptake of parenteral omega-3 rich lipid emulsion fatty acids in patients with advanced pancreatic cancer.

BACKGROUND & AIMS: Omega-3 rich fatty acids (n-3FA) have powerful anti-inflammatory and anti-neoplastic properties. Previous studies have investigated plasma and cellular uptake of oral and parenteral n-3FA regimens. These have shown that n-3FA undergo rapid uptake into cells which is sustained for the length of the treatment course. The aim of this study was to investigate long-term uptake of prolonged, regular treatment courses of parenteral n-3FA which has not been previously reported. METHODS: As part of a phase II single-arm trial, patients with advanced pancreatic cancer were treated with gemcitabine plus parenteral n-3FA rich lipid emulsion (up to 100 g) each week for three consecutive weeks with a subsequent rest week. This was repeated for up to six months in total for each patient. Pre-treatment serum and erythrocyte cell membrane (ECM) pellet samples were obtained each week for the entire treatment course of each patient. Post-treatment samples were obtained for the first two cycles only to assess rapid uptake. Fatty acid methyl esters (FAME) were produced and analysed using gas chromatography. FAME proportions as a total of sample lipid composition for each class were plotted and the results analysed using a linear regression coefficient model. RESULTS: There was rapid and significant uptake of EPA and DHA FAME into plasma Non-Esterified Fatty Acids (NEFA) and EPA into ECM pellets in post-treatment samples (median increase of 1.06%, 0.65% and 0.05% respectively). There was significant reduction in n-6 fatty acid FAMEs and DHA in ECM pellets (decrease of 0.31% and 0.8% respectively- p = 0.031 for all). There was significant sustained uptake of EPA and DHA FAME into ECM pellets over the cohort's pooled treatment course with corresponding reduction in the n-6:n-3 ratio. CONCLUSIONS: Prolonged regular parenteral n-3FA administration results in rapid and sustained cellular uptake. This regimen is appropriate for therapies aimed at increasing n-3FA content of cellular membranes and reduction of the n-6:n-3 ratio.

Can enhanced recovery programmes be further improved by the addition of omega three fatty acids?

AIMS: The term "enhanced recovery programme (ERP)" means applying defined protocols to augment the recovery of patients following surgery. Inflammation is body's response to insults such as infection, injury and surgical procedures. Inflammatory mediators whose function is initially protective may cause undesirable consequences, if the response is unnecessarily prolonged. The principle effects of ERP result from the reduction of the profound stress which results following major surgical procedures. METHODS: A Pubmed literature search was undertaken using the keywords enhanced recovery, surgery and omega-3. The primary endpoint was whether the addition of omega-3 to ERP improved morbidity and mortality. RESULTS: Nine randomised trials examining the effect of omega-3 enriched diets following surgery were analysed. Inclusion of omega-3 helps in maintaining a positive nitrogen balance, overcome immune dysfunction, lower the incidence of post-operative infections with the consequence of reduced morbidity and mortality. CONCLUSIONS: The provision of early or continuous nutrition is one of the cornerstones of an ERP. A theoretically ideal regimen would provide an energy substrate and protein and contain a component which would limit inappropriate inflammation. The beneficial role of omega-3 results from a number of effects which limit the inflammatory response, principally by influencing the production of eicosanoids and modulating cytokines. They also enhance cell-mediated immunity and preserve immune function better than standard dietary formulations. Although ERPs have already produced significant progress, there is sufficient evidence to suggest that the provision of omega-3 fatty acids may result in further improvements.

The difficulties of clinical trials evaluating therapeutic agents in patients with severe sepsis.

INTRODUCTION: Although the pathophysiology of sepsis has been extensively studied, the disease remains a common cause of death in the critically ill patient. It thus remains one of the most pressing clinical and economic problems of modern medicine. A vast amount of inflammatory mediators have been identified as key factors in driving sepsis. Therapeutic agents designed to target these mediators have so far failed to demonstrate significant clinical benefit. METHODS: Clinical trials are the standard for assessing safety and efficacy of novel agents but are made difficult by the heterogeneous nature of septic patients. This review aims to highlight the complex nature of sepsis and the inherent difficulties encountered in designing clinical trials in these patients. The major factors contributing to the difficulties in improving internal and external validity will be discussed with the aim of guiding future study design. CONCLUSIONS: The design of clinical trials on the septic patient remains a challenge. Methodology must be rigorous if seemingly positive clinical trials which are widely implemented are later discredited as a result of poor study design. Many lessons can be learnt from the study design of the PROWESS trial, however there remains room for improvement. This review serves as a stimulus and guide in motivating much needed high quality clinical trials in sepsis.

Biomarkers for the differentiation of sepsis and SIRS: the need for the standardisation of diagnostic studies.

INTRODUCTION: Sepsis is a leading cause of death in the critically ill patient. It is a heterogeneous disease and it is frequently difficult to make an unequivocal and expeditious diagnosis. The current 'gold standard' in diagnosing sepsis is the blood culture but this is only available after a significant time delay. Mortality rates from sepsis remain high, however, the introduction of sepsis care bundles in its management has produced significant improvements in patient outcomes. Central to goal-directed resuscitation is the timely and accurate diagnosis of sepsis. The rapid diagnosis and commencement of the appropriate therapies has been shown to reduce the mortality. MATERIALS AND METHODS: Biomarkers are already used in clinical practice to aid other more traditional diagnostic tests. In the absence of an adequate gold standard to diagnose sepsis, there has been considerable and growing interest in trying to identify suitable biomarkers. There is currently an unmet need in the medical literature to communicate the importance of the challenges relating to the rapid diagnosis and implementation of goal-directed therapy in sepsis and the underlying concepts that are directing these investigations. This article reviews the more novel biomarkers investigated to differentiate systemic inflammatory response syndrome from sepsis. CONCLUSION: The biomarkers described reflect the difficulties in making evidence-based recommendations particularly when interpreting studies where the methodology is of poor quality and the results are conflicting. We are reminded of our responsibilities to ensure high quality and standardised study design as articulated by the STAndards for the Reporting of Diagnostic accuracy studies (STARD) initiative.