Martina Barbara Schaefer

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

Purpose of reviewThe 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. Recent findingsN-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. SummaryN-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.

Acute Lung Injury Is Reduced in fat-1 Mice Endogenously Synthesizing n-3 Fatty Acids

RATIONALE Acute lung injury (ALI) remains an important cause of mortality in intensive care units. Inflammation is controlled by cytokines and eicosanoids derived from the n-6 fatty acid (FA) arachidonic acid (AA). The n-3 FA eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and mediators derived from EPA and DHA possess reduced inflammatory potency. OBJECTIVES To determine whether the ability of fat-1 mice to endogenously convert n-6 to n-3 FA, and thus generate an increased ratio of n-3 to n-6 FA, impacts experimental ALI. METHODS We investigated ALI induced by intratracheal instillation of endotoxin in fat-1 and wild-type (WT) mice, assessing leukocyte numbers, protein concentration, and prostaglandin and cytokine levels in bronchoalveolar lavage fluid, as well as free FA in plasma, and lung ventilator compliance. Body temperature and motor activity of mice--markers of sickness behavior--were also recorded. MEASUREMENTS AND MAIN RESULTS In ALI, fat-1 mice exhibited significantly reduced leukocyte invasion, protein leakage, and macrophage inflammatory protein-2 and thromboxane B(2) levels in lavage fluid compared with WT mice. Free AA levels were increased in the plasma of WT mice in response to endotoxin, whereas EPA and DHA were increased in the fat-1 group. Ventilator compliance was significantly improved in fat-1 mice. Body temperature and motor activity were decreased in ALI. fat-1 Mice recovered body temperature and motor activity faster. CONCLUSIONS fat-1 Mice exhibited reduced features of ALI and sickness behavior. Increasing the availability of n-3 FA may thus be beneficial in critically ill patients with ALI.

cAMP Phosphodiesterase Inhibitors Increases Nitric Oxide Production by Modulating Dimethylarginine Dimethylaminohydrolases

Background— Pulmonary arterial hypertension is characterized by a progressive increase in pulmonary vascular resistance caused by endothelial dysfunction, inward vascular remodeling, and severe loss of precapillary pulmonary vessel cross-sectional area. Asymmetrical dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, and its metabolizing enzyme dimethylarginine dimethylaminohydrolase (DDAH) play important roles in endothelial dysfunction. We investigated whether combined phosphodiesterase (PDE) 3 and 4 inhibition ameliorates endothelial function by regulating the ADMA-DDAH axis. Methods and Results— We investigated the effects of the PDE3/4 inhibitor tolafentrine in vitro on endothelial cell survival, proliferation, and apoptosis. Effects of tolafentrine on the endothelial nitric oxide synthase/nitric oxide pathway, DDAH expression, DDAH promoter activity, and cytokine release from endothelial cells and their subsequent influence on DDAH expression were investigated. In monocrotaline-induced pulmonary arterial hypertension in rats, the effects of inhaled tolafentrine on DDAH expression and activity were investigated. Real-time-polymerase chain reaction, immunocytochemistry, and PDE activity assays suggested high expression of PDE3 and PDE4 isoforms in endothelial cells. Treatment of endothelial cells with PDE3/4 inhibitor significantly decreased ADMA-induced apoptosis via a cAMP/PKA-dependent pathway by induction of DDAH2. Chronic nebulization of PDE3/4 inhibitor significantly attenuated monocrotaline-induced hemodynamic, gas exchange abnormalities, vascular remodeling, and right heart hypertrophy. Interestingly, PDE3/4 inhibitor treatment reduced ADMA and elevated nitric oxide/cGMP levels. Mechanistically, this could be attributed to direct modulatory effects of cAMP on the promoter region of DDAH2, which was consequently found to be increased in expression and activity. Furthermore, PDE3/4 inhibitor suppressed apoptosis in endothelial cells and increased vascularization in the lung. Conclusion— Combined inhibition of PDE3 and 4 regresses development of pulmonary hypertension and promotes endothelial regeneration by modulating the ADMA-DDAH axis.

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

Objective: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. Design:We investigated the impact of lipid emulsions on leukocyte invasion, protein leakage, and cytokines in two murine models of acute inflammation. Setting:Research laboratory of a university hospital. Subjects:Wild-type mice and PAF-receptor knockout mice. Interventions:Mice received an infusion of normal saline, fish oil- or soybean oil-based lipid emulsions before lipopolysaccharide challenge. Measurements and Main Results:Preinfusion with soybean oil resulted in increased leukocyte invasion, myeloperoxidase activity, and protein leakage and exaggerated release of tumor necrosis factor (TNF)-&agr; 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-&agr; 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-&agr; 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. Conclusions: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.

Immunomodulation by fish-oil containing lipid emulsions in murine acute respiratory distress syndrome

IntroductionAcute respiratory distress syndrome (ARDS) is a major cause of mortality in intensive care units. Patients with ARDS often require parenteral nutrition with lipid emulsions as essential components. Besides being an energy supply, these lipid emulsions might display differential modulatory effects on lung integrity and inflammation.MethodsIn a pre-emptive strategy, we investigated the impact of three different intravenously infused lipid emulsions on lung morphology, leukocyte invasion, protein leakage and cytokines in a murine model of ARDS. Mice received an infusion of normal saline solution, a pure long-chain triglycerides (LCT) emulsion, a medium-chain triglycerides (MCT) containing mixed emulsion (LCT/MCT), or a fish oil (FO) containing mixed emulsion (LCT/MCT/FO) before lipopolysaccharide (LPS) challenge.ResultsMice pre-infused with fish oil-containing lipid emulsion showed decreased leukocyte invasion, protein leakage, myeloperoxidase activity, and cytokine production in their alveolar space after LPS challenge compared to mice receiving LCT or LCT/MCT. In line with these findings, lung morphology assessed by histological staining after LPS-induced lung injury improved faster in the LCT/MCT/FO group. Concerning the above mentioned parameters, no significant difference was observed between mice infused with LCT or the combination of LCT and MCT.ConclusionFish oil-containing lipid emulsions might exert anti-inflammatory and pro-resolving effects in the murine model of acute lung injury. Partial replacement of n-6 fatty acids with n-3 fatty acids may thus be of benefit for critically ill patients at risk for ARDS which require parenteral nutrition.

Induction of lymphocyte apoptosis in a murine model of acute lung injury--modulation by lipid emulsions.

Acute lung injury (ALI) and sepsis are the major causes of mortality in intensive care units. Lymphocytes apoptosis is a hallmark feature of late detrimental sepsis. Parenteral nutrition in critically ill patients is based on lipid emulsions, but the impact of ALI and lipid emulsions on lymphocytes has not been defined. The effects of intravenously infused conventional soybean oil (SO)-based and new olive oil (OO)-based emulsions on splenic and blood lymphocytes were investigated in a murine model of endotoxin-induced ALI. After LPS challenge and infusion of lipid emulsions, apoptosis of lymphocytes and lung injury were assessed by flow cytometry, Western blot, and histology. Induction of ALI led to a time-dependent decline in splenic and circulating lymphocyte numbers and an increase in apoptosis, with engagement of the extrinsic apoptotic pathway. Both SO- and OO-based emulsions promoted the apoptosis of splenic lymphocytes before induction of ALI. The OO-based emulsions exhibited lower proapoptotic activity than did SO-based emulsions, an observation paralleled by the induction of survival factors. Induction of ALI increased the mortality of mice receiving SO-based emulsions compared with OO-based emulsions and normal saline. Splenic lymphocyte apoptosis is apparent in murine ALI, which may be linked to detrimental outcome. Infusion of lipid emulsions per se provoked splenic lymphocyte apoptosis. Infusion of SO-based emulsions further augmented the apoptosis of splenic and circulating lymphocytes in ALI and led to increased mortality in mice. These findings may be of relevance for patients experiencing ALI that require parenteral nutrition.

Lipopolysaccharide-induced proliferation and adhesion of U937 cells to endothelial cells involves barium chloride sensitive hyperpolarization

The adhesion of monocytes to the endothelium and their proliferation in the subendothelial space play an important role in atherosclerosis. Since the proliferation and migration of cells are influenced by the activity of ion channels, the aim of this study was to examine whether barium chloride (Ba2+)-sensitive potassium channels (KiCa) are involved in lipopolysaccharide (LPS)-induced proliferation of monocytic U937 cells, and in the adhesion of these cells to endothelial cells. The adhesion of LPS-stimulated U937 cells to endothelial cells reached a maximum at a concentration of 5 µg/ml. This effect of LPS was completely abolished in the presence of Ba2+ (100 µmol/l). In addition, LPS-induced proliferation was significantly reduced by Ba 2+ (control, 100%; LPS 5 µg/ml, 175%; LPS + Ba2+ 100 µmol/l, 136%; n = 12, P < 0.05). To examine whether KiCa are activated by LPS, changes of U937 membrane potential were determined. LPS (5 µg/ml) caused a hyperpolarization of U937 cells indicating a flux of K+ ions out of the cells. This effect was completely blocked by Ba2+ (100 µmol/l). In conclusion, we demonstrate that LPS activates KiCa in U937 cells, which is responsible for LPS-induced adhesion of these cells to endothelial cells, and to the proliferation of U937 cells.

Ernährung und Immunonutrition bei Sepsis

ZusammenfassungDie Ernährungstherapie bei Intensivpatienten ist mehr als die Zufuhr von Kalorien. Nicht alle Konzepte der Ernährung aus der allgemeinen Intensivmedizin sind direkt auf septische Patienten übertragbar. Eine enge Glukosekontrolle durch intensivierte Insulintherapie, erfolgreich bei postoperativen Intensivpatienten angewandt, muss für septische Patienten modifiziert werden. Die Ernährung mit enteraler Immunonutrition, die bei postoperativen Patienten zu einer Verminderung der Liegezeiten führte, kann bei Patienten mit schwerer Sepsis zu einer Erhöhung der Mortalität führen. Für die parenterale Ernährung stehen weiter entwickelte Lipidemulsionen zur Verfügung, die wahrscheinlich Vorteile für den septischen Patienten mit sich bringen. Die intravenöse Supplementierung von langfristig rein parenteral ernährten Intensivpatienten mit Glutamin kann möglicherweise die Sterblichkeit verringern. Insgesamt ist eine individuell optimierte und an die Erkrankung angepasste Ernährung als adjunkte Therapieform ein wichtiger Baustein des Gesamttherapiekonzepts der Sepsis.AbstractNutrition in septic patients is more than just caloric support. Not all nutritional concepts in general intensive care may be applied to septic patients. A tight glycemic control successfully used in post-operative intensive care patients has to be modified for the septic patient. Enteral immunonutrition leading to reduced length of stay in post-operative patients may be associated with increased mortality in patients suffering from severe sepsis. Newly developed lipid emulsions for parenteral nutrition became available. Application of these emulsions may prove to be beneficial in septic patients. An intravenous supplementation with glutamine of long-term exclusively parenterally fed intensive care patients may reduce their mortality. A nutrition individually optimized and adapted to the severity of the disease is considered to be an adjunct therapeutic measure in the treatment concept in sepsis.Nutrition in septic patients is more than just caloric support. Not all nutritional concepts in general intensive care may be applied to septic patients. A tight glycemic control successfully used in post-operative intensive care patients has to be modified for the septic patient. Enteral immunonutrition leading to reduced length of stay in post-operative patients may be associated with increased mortality in patients suffering from severe sepsis. Newly developed lipid emulsions for parenteral nutrition became available. Application of these emulsions may prove to be beneficial in septic patients. An intravenous supplementation with glutamine of long-term exclusively parenterally fed intensive care patients may reduce their mortality. A nutrition individually optimized and adapted to the severity of the disease is considered to be an adjunct therapeutic measure in the treatment concept in sepsis.

Ernährung und Immunonutrition bei Sepsis@@@Nutrition and immunonutrition in septic patients

ZusammenfassungDie Ernährungstherapie bei Intensivpatienten ist mehr als die Zufuhr von Kalorien. Nicht alle Konzepte der Ernährung aus der allgemeinen Intensivmedizin sind direkt auf septische Patienten übertragbar. Eine enge Glukosekontrolle durch intensivierte Insulintherapie, erfolgreich bei postoperativen Intensivpatienten angewandt, muss für septische Patienten modifiziert werden. Die Ernährung mit enteraler Immunonutrition, die bei postoperativen Patienten zu einer Verminderung der Liegezeiten führte, kann bei Patienten mit schwerer Sepsis zu einer Erhöhung der Mortalität führen. Für die parenterale Ernährung stehen weiter entwickelte Lipidemulsionen zur Verfügung, die wahrscheinlich Vorteile für den septischen Patienten mit sich bringen. Die intravenöse Supplementierung von langfristig rein parenteral ernährten Intensivpatienten mit Glutamin kann möglicherweise die Sterblichkeit verringern. Insgesamt ist eine individuell optimierte und an die Erkrankung angepasste Ernährung als adjunkte Therapieform ein wichtiger Baustein des Gesamttherapiekonzepts der Sepsis.AbstractNutrition in septic patients is more than just caloric support. Not all nutritional concepts in general intensive care may be applied to septic patients. A tight glycemic control successfully used in post-operative intensive care patients has to be modified for the septic patient. Enteral immunonutrition leading to reduced length of stay in post-operative patients may be associated with increased mortality in patients suffering from severe sepsis. Newly developed lipid emulsions for parenteral nutrition became available. Application of these emulsions may prove to be beneficial in septic patients. An intravenous supplementation with glutamine of long-term exclusively parenterally fed intensive care patients may reduce their mortality. A nutrition individually optimized and adapted to the severity of the disease is considered to be an adjunct therapeutic measure in the treatment concept in sepsis.Nutrition in septic patients is more than just caloric support. Not all nutritional concepts in general intensive care may be applied to septic patients. A tight glycemic control successfully used in post-operative intensive care patients has to be modified for the septic patient. Enteral immunonutrition leading to reduced length of stay in post-operative patients may be associated with increased mortality in patients suffering from severe sepsis. Newly developed lipid emulsions for parenteral nutrition became available. Application of these emulsions may prove to be beneficial in septic patients. An intravenous supplementation with glutamine of long-term exclusively parenterally fed intensive care patients may reduce their mortality. A nutrition individually optimized and adapted to the severity of the disease is considered to be an adjunct therapeutic measure in the treatment concept in sepsis.

Nutrition and immunonutrition in septic patients

ZusammenfassungDie Ernährungstherapie bei Intensivpatienten ist mehr als die Zufuhr von Kalorien. Nicht alle Konzepte der Ernährung aus der allgemeinen Intensivmedizin sind direkt auf septische Patienten übertragbar. Eine enge Glukosekontrolle durch intensivierte Insulintherapie, erfolgreich bei postoperativen Intensivpatienten angewandt, muss für septische Patienten modifiziert werden. Die Ernährung mit enteraler Immunonutrition, die bei postoperativen Patienten zu einer Verminderung der Liegezeiten führte, kann bei Patienten mit schwerer Sepsis zu einer Erhöhung der Mortalität führen. Für die parenterale Ernährung stehen weiter entwickelte Lipidemulsionen zur Verfügung, die wahrscheinlich Vorteile für den septischen Patienten mit sich bringen. Die intravenöse Supplementierung von langfristig rein parenteral ernährten Intensivpatienten mit Glutamin kann möglicherweise die Sterblichkeit verringern. Insgesamt ist eine individuell optimierte und an die Erkrankung angepasste Ernährung als adjunkte Therapieform ein wichtiger Baustein des Gesamttherapiekonzepts der Sepsis.AbstractNutrition in septic patients is more than just caloric support. Not all nutritional concepts in general intensive care may be applied to septic patients. A tight glycemic control successfully used in post-operative intensive care patients has to be modified for the septic patient. Enteral immunonutrition leading to reduced length of stay in post-operative patients may be associated with increased mortality in patients suffering from severe sepsis. Newly developed lipid emulsions for parenteral nutrition became available. Application of these emulsions may prove to be beneficial in septic patients. An intravenous supplementation with glutamine of long-term exclusively parenterally fed intensive care patients may reduce their mortality. A nutrition individually optimized and adapted to the severity of the disease is considered to be an adjunct therapeutic measure in the treatment concept in sepsis.Nutrition in septic patients is more than just caloric support. Not all nutritional concepts in general intensive care may be applied to septic patients. A tight glycemic control successfully used in post-operative intensive care patients has to be modified for the septic patient. Enteral immunonutrition leading to reduced length of stay in post-operative patients may be associated with increased mortality in patients suffering from severe sepsis. Newly developed lipid emulsions for parenteral nutrition became available. Application of these emulsions may prove to be beneficial in septic patients. An intravenous supplementation with glutamine of long-term exclusively parenterally fed intensive care patients may reduce their mortality. A nutrition individually optimized and adapted to the severity of the disease is considered to be an adjunct therapeutic measure in the treatment concept in sepsis.