1、N-3 Lipids in Critical Care Medicine Dr.Konstantin Mayer University of Giessen Lung Center Pulmonary and Critical Care Medicine University Hospital Giessen and Marburg Lipid Mediator Synthesis AA(-6)-degranulation leakage -adhesion vasoconstriction PMN-activationpostkapillary LOCOLTE4 LTD4LTB4LTC4PG
2、I2TxA2vasodilatation vasoconstriction 5,6-EET8,9-EET11,12-EET14,15-EETvasodilatation(?)other effects?EDHF(?)P450Impact of n-3 vs.n-6 Fatty Acids on Inflammation Key Features of Acute Lung Injury pulmonary hypertension VQ-mismatch/Shunt vasomotor dysfunction vascular leakage gas exchange secundary ba
3、cterial invasion Q O2 O2 O2 leukocyte invasion Capillary sequestration Alveolar invasion N-3 Lipids Randomized,controlled study 21 Pts with septic ARDS LCT or LCT/MCT 12g/h Pulmonary hemodynamics/Ventilation parameter Results LCT(n-6)Increase in Pulmonary Artery Pressure(MPAP)Decrease in Oxygenation
4、-Index(PaO2/FiO2)0204060dPAP mm Hg10-910-810-710-610-5Concentration mol/lInfluence of Free Fatty Acids onPulmonary Artery PressureTxA2=108 pg/mlTxA3=60g)Influence of Free Fatty Acids on Vascular Leakage in a Septic Lung ModelF.Grimminger et al,Am J Resp Crit Care Med,1997,155:513-9Protective impact
5、of n-3 fatty acids on edema-formation in a model of septic lung failure LTB4+LTB4+LTB4+LTB5+Effects of Parenteral Application of Fish Oil versus Soy Bean Oil Emulsions on Bacterial Clearance Functions I.Kelbel,T.Koch,A.Prechtl,A.Heller,E.Schlotzer,H.G.Schiefer,H.Neuhof Infusion Therapy&Transfusion M
6、edicine:26,226-232,1999 Experimental Protocol(Kelbel et al.,1999)Design:36 rabbits,randomly assigned to 6 groups Treatment:1.5 g/kg b.w./day for 3 days of a -fish oil emulsion(n-3 rich)-a soybean oil emulsion(n-6 rich)or -0.9%saline(Control)E.coli intravenous injection(1.3 x 108 CFU)Sacrifice of ani
7、mals 3 or 6 h after bact.injection Parameters:Bacterial counts in lung,liver,spleen&kidney Number of bacterial colonies in the lung Kelbel et al.1999 Long-term lipid-infusion in mice Leukocyte Invasion in a Model of Acute Lung Injury Impact of n-3 Lipids 0123Leukocytes in BAL x 106cellsNaCln-3 n-6Na
8、Cln-3 n-6NaCln-3 n-6NaCln-3 n-6WTPAF-R-/-BNLPS*Crit Care Med 2007 BAL Broncho alveolar lavage LPS lipopolysaccharide Enteral n-3 lipids+anti-oxidants:N-3 Lipids&ARDS RCT of 146 critically ill patients acute lung injury and positive bronchoalveolar lavage for leukocytes Double-blinded Enteral:N-3 Lip
9、ids vs.high fat diet Gadek,Crit Care Med 1999;27:1409 ARDS Enteral n-3 Lipids 05101520daysventilatordaysICUdaysControlEPA+GLAp=0.11p=0.16Adapted from:Gadek JE.et al.,Crit Care Med 1999;27:1409-20 p=.011 p=.016 Do lipids modulate acute lung injury?Should we have faith in fat?Key Features of ARDS pulm
10、onary hypertension VQ-mismatch/Shunt vasomotor dysfunction vascular leakage gas exchange secundary bacterial invasion Q O2 O2 O2 leukocyte invasion Capillary sequestration Alveolar invasion Lipid emulsions are a mainstay of parenteral nutrition used in many ventilated patients with acute lung injury
11、 Immunologic Effects of lipid emulsions in ARDS n-3 lipids may have beneficial effects in ARDS in contrast to n-6 lipids.SCCM+Canadian Guidelines:N-3+ARDS:Grade A recommendation N-3 lipids and bacterial translocation/bacterial killing?Endo/Exotoxin Focus Bacterial translocation nosocomial Pneumonia
12、1.barrier dysfunction Gut 2.barrier dysfunction Improvement of blood flow in the intestine in endotoxic rats by n-3 lipids L=SBO L-M=SBO+MCT FO-20=L-M+FO(20%)FO-40=L-M+FO(40%)Pscheidl,E et al Improvement of bacterial killing in the liver in endotoxic rats by n-3 lipids L=SBO L-M=SBO+MCT FO-20=L-M+FO
13、(20%)FO-40=L-M+FO(40%)Pscheidl,E et al Impact of Fish Oil on LPS-induced Response in Volunteers 8 volunteers 0.5 g/kg/d FO for 2 d 8 volunteers no infusion LPS 2 ng/kg intravenous readout:cytokines,hormones,RR,HF,temperature,Pluess T et al.,Intensive Care Med.2007;33(5):789-97 Fish Oil reduces LPS-i
14、nduced fever-response in volunteers Effect of SBO-based lipids Increased inflammatory response Reduced bacterial killing/clearance Increased primary/seconday organ damage May translate into clinical effects SIRS CARS Biphasic reaction of leukocytes in septic patients Hyper Hypo Effective Response Ma
15、yer,Curr Opin Clin Nutr Metab Care 1998 SIRS:systemic inflammatory response syndrome CARS:compensatory anti-inflammatory response syndrome Design:open label,randomized,pilot study Setting:Intensive Care Unit Patients:10 septic shock patients,8 healthy controls Nutrition:Parenteral nutrition over 10
16、days,total lipid intake 0.5 g/kg b.w./d Groups:1)Control:LCT 10%2)FO 10%Parameters:FFA,Leukotrienes,PAF,Thromboxane,.Mayer,K et al Infection Sepsis Free Fatty Acids:Lipid Emulsions and Intensive Care Free Fatty Acids Triglycerides LPL Heparin Lipid Mediatores J Am Acad Dermatol 1998 Intensive Care Med 2003 Impact of Sepsis and Infusion of Lipid Emulsions on Free Fatty Acids 020406080100AA 祄ol/l0306090120150EPA 祄ol/lPsoriasispost-infusionSepsispost-infusionPsoriasispost-infusionSepsispost-infusio
