1、N-3 Lipids in Critical Care MedicineDr.Konstantin MayerUniversity of Giessen Lung CenterPulmonary and Critical Care MedicineUniversity Hospital Giessen and MarburgLipid Mediator SynthesisAA(-6)-degranulation leakage -adhesion vasoconstriction PMN-activationpostkapillary LOCOLTE4 LTD4LTB4LTC4PGI2TxA2
2、vasodilatation vasoconstriction 5,6-EET8,9-EET11,12-EET14,15-EETvasodilatation(?)other effects?EDHF(?)P450Impact of n-3 vs.n-6 Fatty Acids on InflammationClinical CourseKey Features of ARDSAdapted from:Gadek JE.Enteral:N-3 Lipids vs.,Crit Care Med 1999;27:1409-20Am J Resp Cell Mol Biol 1997Addition
3、of FO(0.dysfunctionLipid emulsions are a mainstay of parenteral nutrition,Crit Care Med 1999;27:1409-208 volunteers no infusioncoli intravenous injection(1.Clinical CourseFO-20=L-M+FO(20%)J Am Acad Dermatol 1998PaO2/Fi02=60 mmHg,further detoriationConclusion:Sepsis+n-3 lipidsleukocyte invasionKey Fe
4、atures of Acute Lung Injury pulmonary hypertension VQ-mismatch/Shuntvasomotor dysfunction vascular leakagegas exchange secundary bacterial invasionQO2O2O2 leukocyte invasionCapillary sequestrationAlveolar invasionN-3 Lipids Randomized,controlled study 21 Pts with septic ARDS LCT or LCT/MCT 12g/h Pul
5、monary hemodynamics/Ventilation parameterResultsLCT(n-6)Increase in Pulmonary Artery Pressure(MPAP)Decrease in Oxygenation-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 A
6、cids on Vascular Leakage in a Septic Lung ModelF.Grimminger et al,Am J Resp Crit Care Med,1997,155:513-9Protective impact of n-3 fatty acidson edema-formation in a model of septic lung failureLTB4+LTB4+LTB4+LTB5+Effects of Parenteral Application ofFish Oil versus Soy Bean Oil Emulsionson Bacterial C
7、learance FunctionsI.Kelbel,T.Koch,A.Prechtl,A.Heller,E.Schlotzer,H.G.Schiefer,H.Neuhof Infusion Therapy&Transfusion Medicine:26,226-232,1999Experimental Protocol(Kelbel et al.,1999)Design:36 rabbits,randomly assigned to 6 groupsTreatment:1.5 g/kg b.w./day for 3 days of a-fish oil emulsion(n-3 rich)-
8、a soybean oil emulsion(n-6 rich)or-0.9%saline(Control)E.coli intravenous injection(1.3 x 108 CFU)Sacrifice of animals 3 or 6 h after bact.injectionParameters:Bacterial counts in lung,liver,spleen&kidneyNumber of bacterial colonies in the lungKelbel et al.1999Design:36 rabbits,randomly assigned to 6
9、groupsUniversity Hospital Giessen and MarburgImprovement of bacterial killing in the liver in endotoxic rats by n-3 lipidsUniversity of Giessen Lung CenterEffect of SBO-based lipidsImpact of Sepsis and Infusion of Lipid Emulsions on Free Fatty AcidsLong-term lipid-infusion in miceLeukocyte Invasion
10、in a Model of Acute Lung Injury Impact of n-3 Lipids0123Leukocytes in BAL x 106cellsNaCln-3 n-6NaCln-3 n-6NaCln-3 n-6NaCln-3 n-6WTPAF-R-/-BNLPS*Crit Care Med 2007BALBroncho alveolar lavageLPSlipopolysaccharideEnteral n-3 lipids+anti-oxidants:N-3 Lipids&ARDS RCT of 146 critically ill patients acute l
11、ung injury and positive bronchoalveolar lavage for leukocytes Double-blinded Enteral:N-3 Lipids vs.high fat diet Gadek,Crit Care Med 1999;27:1409ARDS Enteral n-3 Lipids05101520daysventilatordaysICUdaysControlEPA+GLAp=0.11p=0.16Adapted from:Gadek JE.et al.,Crit Care Med 1999;27:1409-20p=.011p=.016Do
12、lipids modulate acute lung injury?Should we have faith in fat?Key Features of ARDS pulmonary hypertension VQ-mismatch/Shuntvasomotor dysfunction vascular leakagegas exchange secundary bacterial invasionQO2O2O2 leukocyte invasionCapillary sequestrationAlveolar invasionLipid emulsions are a mainstay o
13、f parenteral nutritionused in many ventilated patients with acute lung injuryImmunologic 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 recommendationN-3 lipids and bacterial translocation/bacteria
14、l killing?Endo/ExotoxinFocusBacterialtranslocationnosocomialPneumonia1.barrier dysfunctionGut2.barrier dysfunctionImprovement of blood flow in the intestine in endotoxic rats by n-3 lipidsL=SBOL-M=SBO+MCTFO-20=L-M+FO(20%)FO-40=L-M+FO(40%)Pscheidl,E et alImprovement of bacterial killing in the liver
15、in endotoxic rats by n-3 lipidsL=SBOL-M=SBO+MCTFO-20=L-M+FO(20%)FO-40=L-M+FO(40%)Pscheidl,E et alImpact 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.,I
16、ntensive Care Med.2007;33(5):789-97Fish Oil reduces LPS-induced fever-response in volunteersEffect of SBO-based lipids Increased inflammatory response Reduced bacterial killing/clearance Increased primary/seconday organ damage May translate into clinical effectsSIRSCARSBiphasic reaction of leukocyte
17、s in septic patientsHyperHypoEffective ResponseMayer,Curr Opin Clin Nutr Metab Care 1998 SIRS:systemic inflammatory response syndromeCARS:compensatory anti-inflammatory response syndromeDesign:open label,randomized,pilot studySetting:Intensive Care UnitPatients:10 septic shock patients,8 healthy con
18、trolsNutrition:Parenteral nutrition over 10 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 alInfectionSepsisFree Fatty Acids:Lipid Emulsions and Intensive CareFree Fatty AcidsTriglyceridesLPLHeparinLipid MediatoresJ Am
19、Acad Dermatol 1998Intensive Care Med 2003Impact of Sepsis and Infusion of Lipid Emulsions on Free Fatty Acids020406080100AA mol/l0306090120150EPA mol/lPsoriasispost-infusionSepsispost-infusionPsoriasispost-infusionSepsispost-infusion*5-Lipoxygenase Metabolism in PMN5 5-L LO ON N e eu ut tr ro op ph
20、hi i l l*availability of free fatty acid(AA/EPA)*Eicosapentaenoic acid is the preferred substrateDesign:controlled,randomised studySetting:Intensive Care UnitPatients:21 septic shock patients,6 healthy controlsNutrition:Parenteral nutrition over 5 days,total lipid intake 0.5 g/kg b.w./d Groups:1)Con
21、trol:LCT 10%2)FO 10%Parameters:FFA,CytokinesMayer,K et al05000100001500020000pg/5x106 MNL123456time d1118w-6/LPSw-3/LPScontrol/LPSw-3/-w-6/-control/-IL-1n=9n=85n=4n=4n=6lipid infusionLPS-induced IL-1 Secrection in MNLInfluence of Lipid Infusions in Septic PatientsMayer 2003,Am J Resp Crit Care MedMa
22、yer,Curr Opin Clin Nutr 2006Biochemical Background Use of RvE1 in a Colitis-Model Read-out:Letality,weight,histology inflammatory genesMayer,Curr Opin Clin Nutr 2006Impact of n-3 Lipids on Immunity Female patient,*1939,Arterial hypertension,Smoker,Multiple herniates disks lower back Presented with a
23、cute abdomen Bowel sounds present Pain Tender Abdomen CT thorax+abdomen Exsudative pancreatitis Lung edema transferred to medical intensive care unitClinical Course Upon improvement transfer to step-down unit 3 days later After 2 days development of acute dyspnoea Low blood pressureClinical Course R
24、e-Transfer to intensive care unit Beginning ARDS Severe necrotising pancreatitis(CT)Clinical Course Intubation Difficult respiratory situation FiO2 0,7-1,0;PaO2 50 70 mm Hg;Acute renal failure MODSClinical Course Septic course Addition of FO(0.2 g/kg)i.v.on top of TPN(LCT/MCT 0.7 g/kg)Difficult vent
25、ilation,high oxygen(FiO2=100%,ARDS)Later:low grade enteral nutrition via gastric route installedClinical Course Slow improvement of the patient Improvement of ARDS Sucessful weaning and extubation Discharge of the patient to a rehabilitation facilitySecond case Travel to Italy a week before admittan
26、ce Presented with fever and cough to another hospitalClinical course Development of ARDS Difficult ventilation situation PaO2/Fi02=60 mmHg,further detoriation Installation of ECMO-therapy Received diagnosis of legionella pneumonia due to positive urine test in other hospital Addition of FO on top of
27、 TPN and ENClinical course 07.2007 Gradual improvement with therapy Weaning from ECMO Weaning from ventilation Discharge to rehabilitation centerConclusion:Sepsis+n-3 lipids Beneficial actions of n-3 FA containing lipid emulsions in models of acute lung injury and sepsis Improved organ function/inte
28、grity Improved bacterial killing Improved outcome due to n-3 FA containing diets in patients with acute lung injury and sepsis Possible benefits of n-3 containing lipid emulsions in septic patientsThank you for your attentionResultsLCT(n-6)Increase in Pulmonary Artery Pressure(MPAP)Decrease in Oxyge
29、nation-Index(PaO2/FiO2)ResultsLCT(n-6)Increase in Pulmonary Artery Pressure(MPAP)Decrease in Oxygenation-Index(PaO2/FiO2)Leukocyte Invasion in a Model of Acute Lung Injury Impact of n-3 Lipids0123Leukocytes in BAL x 106cellsNaCln-3 n-6NaCln-3 n-6NaCln-3 n-6NaCln-3 n-6WTPAF-R-/-BNLPS*Crit Care Med 20
30、07BALBroncho alveolar lavageLPSlipopolysaccharideARDS Enteral n-3 Lipids05101520daysventilatordaysICUdaysControlEPA+GLAp=0.11p=0.16Adapted from:Gadek JE.et al.,Crit Care Med 1999;27:1409-20p=.011p=.016Mayer,Curr Opin Clin Nutr 2006Biochemical BackgroundMayer,Curr Opin Clin Nutr 2006Mayer,Curr Opin Clin Nutr 2006
