Fish Oil-based Lipid Emulsion Research Articles

Parenteral Fish Oil as Monotherapy Prevents Essential Fatty Acid Deficiency in Parenteral Nutrition–dependent Patients

The use of fish oil-based emulsions as the sole source of fat for patients receiving parenteral nutrition (PN) has raised concerns for the development of essential fatty acid deficiency (EFAD), hindering its adoption into clinical practice. The purpose of the present study was to examine fatty acid profiles of patients receiving no enteral energy, while completely dependent on PN and an intravenous fish oil-based lipid emulsion, for onset of EFAD and maintenance of growth. Prospectively collected data from 10 patients were reviewed for evidence of EFAD, defined as a triene:tetraene ratio >0.2. Gestational age-adjusted z scores for length, growth, and head circumference at baseline were compared with the corresponding z scores at time of censoring. All of the patients received PN with a fish oil-based lipid emulsion at 1 g . kg . day as the sole source of fat energy for at least 1 month. The fish oil monotherapy was used under a compassionate use protocol. Median gestational age at the time of birth was 35 weeks, and median age at the start of treatment was 3.5 months. After a median time of 3.8 months on exclusive PN and fish oil-based lipid emulsion, none of the patients developed biochemical or clinical evidence of EFAD. z scores were not statistically different, indicating no growth impairment. Median direct bilirubin levels improved in 9 patients from 6.8 to 0.9 mg/dL (P = 0.009). : When dosed appropriately, fish oil-based lipid emulsions contain sufficient amounts of essential fatty acids to prevent EFAD and sustain growth in patients who are completely dependent on PN.

Impact of Fish Oil-Based Lipid Emulsion on Serum Triglyceride, Bilirubin, and Albumin Levels in Children With Parenteral Nutrition-Associated Liver Disease

Parenteral nutrition is known to cause liver injury in babies. The aim of this study is to investigate the effects of different lipid emulsions on parenteral nutrition-associated cholestasis in infants. In addition, there may be a relationship between the lipid emulsion and triglyceride levels. Furthermore, triglyceride levels may correlate with direct bilirubin and albumin, as markers of liver impairment and nutritional status. Patients with parenteral nutrition-associated cholestasis who were treated with a fish oil-based lipid emulsion (n = 18) were prospectively followed for triglyceride, direct bilirubin, and albumin levels and compared with patients who were maintained on a soy-based lipid emulsion (n = 59). Triglyceride levels decreased in the fish oil cohort from a mean of 140 mg/dL at wk 0 to 40 mg/dL at wk 20 but remained unchanged at approximately 140 mg/dL in the soybean cohort. Triglyceride levels of patients treated with fish oil declined over time, while those receiving soybean oil did not. Also, changes in triglyceride levels over time were directly correlated with direct bilirubin and inversely related to albumin levels. These findings may indicate an added benefit of reduced triglyceride levels for patients treated with fish oil and this effect coincides with markers for improved liver function and nutritional status.

Parenteral Fish Oil Improves Outcomes in Patients With Parenteral Nutrition-Associated Liver Injury

The objective was to determine the safety and efficacy of a fish oil-based intravenous lipid emulsion (ILE) in the treatment of parenteral nutrition-associated liver disease (PNALD). PNALD can be a lethal complication in children with short bowel syndrome (SBS). ILE based on soybean oil administered with parenteral nutrition (PN) may contribute to its etiology. We performed an open-labeled trial of a fish oil-based ILE in 42 infants with SBS who developed cholestasis (serum direct bilirubin >2 mg/dL) while receiving soybean oil-based ILE. Safety and efficacy outcomes were compared with those from a contemporary cohort of 49 infants with SBS and cholestasis whose PN course included soybean ILE only. The primary efficacy end-point was time to reversal of cholestasis (direct bilirubin <=2 mg/dL). Three deaths and 1 liver transplantation occurred in the fish oil cohort, compared with 12 deaths and 6 transplants in the soybean oil cohort (P = 0.005). Among survivors not transplanted during PN, cholestasis reversed while receiving PN in 19 of 38 patients in the fish oil cohort versus 2 of 36 patients in the soybean oil cohort. Based on Cox models, subjects receiving fish oil-based ILE experienced reversal of cholestasis 6 times faster (95% CI: 2.0-37.3) than those receiving soybean oil-based ILE. The provision of fish oil-based ILE was not associated with hypertriglyceridemia, coagulopathy, or essential fatty acid deficiency. Moreover, hypertriglyceridemic events and abnormal international normalized ratio levels were more common among controls. Fish oil-based ILE is safe, may be effective in treating PNALD, and may reduce mortality and organ transplantation rates in children with SBS.

Fish Oil–Based Lipid Emulsions Prevent and Reverse Parenteral Nutrition–Associated Liver Disease: The Boston Experience

Parenteral nutrition-associated liver disease (PNALD) is the most prevalent and most severe complication of long-term parenteral nutrition. Its underlying pathophysiology, however, largely remains to be elucidated. The currently approved parenteral lipid emulsions in the United States contain safflower or soybean oils, both rich in omega-6 polyunsaturated fatty acids (PUFAs). Mounting evidence indicates that the omega-6 PUFAs originating from plant oils in these lipid emulsions may play a role in the onset of liver injury. Fish oil-based lipid emulsions, in contrast, are primarily composed of omega-3 PUFAs, thus providing a promising alternative. The authors review the literature on the role of lipid emulsions in the onset of PNALD and discuss prevention and treatment strategies using a fish oil-based lipid emulsion. They conclude that a fish oil-based emulsion is hepatoprotective in a murine model of PNALD, and it appears to be safe and efficacious for the treatment of this type of liver disease in children. A prospective randomized trial that is currently under way at the authors' institution will objectively determine the place of fish oil monotherapy in the prevention of PNALD.

The essentiality of arachidonic acid and docosahexaenoic acid

Objective The purpose of this review is to correlate the clinical finding that patients receiving parenteral nutrition with a fish oil-based lipid emulsion do not develop essential fatty acid deficiency (EFAD) with an experimental murine model, thus showing that arachidonic acid (AA) and docosahexaenoic acid (DHA) are likely to be the essential fatty acids. Background Conventional belief is that linoleic acid (LA, omega-6) and alpha-linolenic acid (ALA, omega-3) are the essential fatty acids (EFAs). We have shown that a fish oil-based lipid emulsion containing AA (omega-6) and docosahexaenoic acid (omega-3) and insignificant quantities of LA and ALA is efficacious in the treatment of parenteral nutrition-associated liver disease (PNALD), a major cause of liver-related morbidity and mortality. The prospect of using a fish oil-based lipid emulsion as monotherapy has raised concerns of EFAD development, hindering its adoption into clinical practice. Design Data from patients in our institution who received PN with a fish oil-based lipid emulsion was reviewed for clinical and biochemical evidence of EFAD, defined as an elevated triene–tetraene ratio (Mead acid/AA>0.2). We also investigated the minimum amount of fish oil required to prevent EFAD in a murine model and determined whether DHA and AA alone can prevent EFAD. Results No patients receiving PN with a fish oil-based lipid emulsion in our institution have developed biochemical or clinical evidence of EFAD such as an elevated triene–tetraene ratio, growth retardation or dermatitis. This observation parallels our previously published animal studies, which demonstrated prevention of EFAD when 13% of total calories were from fish oil. Moreover, current work in our laboratory shows that AA and DHA provision alone is sufficient to prevent biochemical and physiologic evidence of EFAD in a murine model. Conclusions When dosed appropriately, fish oil-based lipid emulsions contain sufficient EFAs to prevent EFAD. Furthermore, AA and DHA alone may be the true EFAs.

Some new insights in intestinal failure-associated liver disease

To point new insights in the cholestasis that is a complication of both intestinal failure and parenteral nutrition. View on liver disease has recently evolved with the onset of fish oil-based intravenous lipid emulsions (ILE). Focused on the role of ILE in causing liver disease. Reversal of cholestasis was recently achieved in infants with short bowel syndrome, by replacing the 'reference' soybean oil-based ILE by fish oil-based ILE. It is likely that this reversal involves several factors such as the change in n-6: n-3 ratio, the reduction in phytosterol load, the increased provision of alpha-tocopherol as antioxidant agent. Alternative issue might be based on the use of a new generation of ILE aiming to provide n-3 and to reduce n-6 fatty acids load while enhancing alpha-tocopherol intake. New data are based on the use of an ILE containing a balanced proportion of four types of oil as a physical mixture of 30% soybean oil, 30% medium-chain triglycerides, 25% olive oil and 15% fish oil with amounts of alpha-tocopherol calculated according to the number of double bonds. This new emulsion was reported to be beneficial in reversing or preventing liver disease.

Fish oil in critical illness

The aim of this review is to discuss recent advances in the role of n-3 lipids derived from fish oil in clinical nutrition in an intensive care setting. Fish oil supplies n-3 fatty acids which compete with arachidonic acid (n-6) for the conversion to lipid mediators, influence lipid-bound second messenger generation and dependent cellular functions, and are a source for resolvins necessary for the resolution of inflammation. Enteral nutrition with n-3 fatty acids improved ventilation time in patients with acute lung injury and in one study reduced mortality in septic patients. Using a high-dose short-term infusion of fish oil-based lipid emulsion, rapid immunologic changes and effects on the endotoxin-induced stress response may be achieved. Inclusion of n-3 fatty acids in parenteral nutrition improved immunologic parameters and length of stay in surgical patients. Inclusion of fish oil in nutrition may influence the immune response and clinical outcomes by balancing the negative effects of n-6 fatty acids. Application as a part of enteral immunonutrition in surgical or acute respiratory distress syndrome patients and in lipid emulsions in surgical patients has beneficial effects. In septic patients, data on enteral use are highly controversial. Prospective data from randomized trials, however, are lacking.

Immunomodulation by n-3- versus n-6-rich lipid emulsions in murine acute lung injury—Role of platelet-activating factor receptor

Cytokines, platelet-activating factor (PAF), and eicosanoids control local and systemic inflammation. Conventional soybean oil-based lipid emulsions used for parenteral nutrition may aggravate the leukocyte inflammatory response or adhesion to the vessel wall. Fish oil-based lipid emulsions, in contrast, may exert an anti-inflammatory effect. We investigated the impact of lipid emulsions on leukocyte invasion, protein leakage, and cytokines in two murine models of acute inflammation. Research laboratory of a university hospital. Wild-type mice and PAF-receptor knockout mice. Mice received an infusion of normal saline, fish oil- or soybean oil-based lipid emulsions before lipopolysaccharide challenge. Preinfusion with soybean oil resulted in increased leukocyte invasion, myeloperoxidase activity, and protein leakage and exaggerated release of tumor necrosis factor (TNF)-alpha as well as macrophage inflammatory protein (MIP)-2 into the alveolar space after intratracheal lipopolysaccharide challenge. In contrast, preinfusion with fish oil reduced leukocyte invasion, myeloperoxidase activity, protein leakage, and TNF-alpha as well as MIP-2 generation. Corresponding profiles were found in plasma following intraperitoneal lipopolysaccharide application: Soybean oil increased but fish oil decreased the TNF-alpha and MIP-2 formation. When PAF-receptor-deficient mice were challenged with lipopolysaccharide, leukocyte invasion, lung tissue myeloperoxidase, cytokine generation, and alveolar protein leakage corresponded to those observed in wild-type animals. Fish oil and soybean oil lost their diverging effects on leukocyte transmigration, myeloperoxidase activity, leakage response, and cytokine generation in these knockout mice. Similarly, the differential impact of both lipid emulsions on these lipopolysaccharide-provoked changes was suppressed after pretreating animals with a PAF-receptor antagonist. Fish oil- vs. soybean oil-based lipid infusions exert anti- vs. proinflammatory effects in murine models of acute inflammation. The PAF/PAF-receptor-linked signaling appears to be a prerequisite for this differential profile.

Fish oil in the critically ill: from experimental to clinical data

The aim of this paper is to describe recent relevant literature concerning the role of n-3 lipids derived from fish oil in clinical nutrition in an intensive care setting. N-3 fatty acids compete with arachidonic acid for metabolism to lipid mediators and exert profound effects on second mediator generation and dependent cellular functions. In experimental models, dietary and parenteral use of fish oil was shown to protect the gut by increasing its perfusion. In contrast, use of immunonutrition including fish oil in critical ill patients or patients with severe sepsis may exert an excess mortality. Using parenteral fish oil in surgical patients promising data became available. In septic patients, immunologic effects of fish oil-based lipid emulsions have been found and intravenous supplementation with fish oil may have a beneficial impact on mortality and length of stay. For both patient groups, however, prospective data from randomized trials are lacking. N-3 lipids exhibit strong immunologic properties. They offer the possibility to counterbalance the negative effects of conventional n-6 fatty acids. Recent studies exhibit positive effects of intravenous use of fish oil on immunologic functions and clinical parameters in surgical and septic patients.

Use of a fish oil-based lipid emulsion to treat essential fatty acid deficiency in a soy allergic patient receiving parenteral nutrition

The treatment of essential fatty acid deficiency (EFAD) in a 17-year-old male following allogeneic bone marrow transplantation is described. His transplant was complicated by gastrointestinal bleeding that precluded the use of enteral feedings. Due to a severe soy allergy, he could not tolerate any intravenous fat emulsions marketed in the US. After months of receiving fat-free parenteral nutrition and intermittent use of enteral feeds, he developed signs and symptoms consistent with EFAD, including a rash and an elevated plasma triene:tetraene ratio of 0.231 (0.013-0.05). After receiving FDA approval, a parenteral fish oil emulsion was administered to provide fat calories and sufficient alpha-linolenic and linoleic acid to correct his EFAD. Therapy was initiated at 0.2 g/kg/day and advanced to 0.67 g/kg/day, providing approximately 45 mg/kg/day of linoleic acid. After 10 days of therapy, his rash disappeared and his triene:tetraene ratio improved to 0.07. By day 17 the ratio normalized to 0.047. This suggests that using a fish oil emulsion with minimal linoleic acid may be safely used as the sole source of fat calories and may be an option to prevent or treat EFAD in subjects allergic to soy that require a parenteral source of fat.

Effect of an omega-3 fatty acid containing lipid emulsion alone and in combination with 5-fluorouracil (5-FU) on growth of the colon cancer cell line Caco-2

In this study we examined the effects of a fish oil-based lipid emulsion (FO) rich in omega-3 fatty acids, which is used in humans as a component of parenteral nutrition, on the growth of the colon cancer cell line Caco-2. The aim of the present study was to investigate whether the FO influences growth and chemosensitivity of the colon cancer cell line Caco-2. FO was tested alone and in combination with the anticancer drug 5-fluorouracil (5-FU). Cell numbers were determined with crystal violet staining, cell cycle distribution was assessed using a flow cytometer and apoptosis was visualized by staining nuclei with diamino-phenylindole hydrochloride. FO inhibited growth of Caco-2 cells in a time and dose dependent manner. FO treatment evoked apoptosis as confirmed by cell morphology. Cell cycle analysis identified an accumulation of cells in the G(2)/M phase after incubation with FO. The combined treatment of the cells with FO and 5-FU resulted in a significant enhancement of the growth inhibition seen after exposure to either substance alone. Treatment of the cells with 5-FU specifically blocked the cell cycle in the S phase. The combined treatment of 5-FU with FO showed a further increase in the accumulation of cells in the S phase. In conclusion, FO has a potent antiproliferative effect on Caco-2 cells, at least in part, due to a decrease in the progression of the cell cycle and the induction of apoptosis. The combination of FO with 5-FU results in an additive growth inhibitory effect.

Effect of emulsifier on oxidation properties of fish oil-based structured lipid emulsions.

The effects of the emulsifiers lecithin, Tween 20, whey protein isolate, mono-/diacylglycerols, and sucrose fatty acid ester on oxidation stability of a model oil-in-water emulsion prepared with enzymatically synthesized menhaden oil-caprylic acid structured lipid were evaluated. Oxidation was monitored by measuring lipid hydroperoxides, thiobarbituric acid reactive substances, and the ratio of combined docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) contents to palmitic acid in the emulsion. After high-pressure homogenization, all emulsions, except those prepared with lecithin, had similar droplet size distributions. All structured lipid emulsions, except for the lecithin-stabilized emulsions, were stable to creaming over the 48-day period studied. Emulsifier type and concentration affected oxidation rate, with 0.25% emulsifier concentration generally having a higher oxidation rate than 1% emulsifier concentration. Overall, oxidation did not progress significantly enough in 48 days of storage to affect DHA and EPA levels in the emulsion.