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1、N3N3脂肪酸在急重症的应脂肪酸在急重症的应用用Lipid Mediator SynthesisImpact of n-3 vs. n-6 Fatty Acids on InflammationKey Features of Acute Lung Injury pulmonary hypertension VQ-mismatch / Shuntvasomotor dysfunction vascular leakagegas exchange secundary bacterial invasionQO2O2O2 leukocyte invasionCapillary sequestratio
2、nAlveolar invasionN-3 LipidsRandomized, controlled study21 Pts with septic ARDS LCT or LCT/MCT 12g/hPulmonary hemodynamics / Ventilation parameterResultsLCT (n-6)Increase in Pulmonary Artery Pressure (MPAP) Decrease in Oxygenation-Index (PaO2 / FiO2)Grimminger, Mayer et al. J Pharm Exp Ther 1993, Am
3、 J Physiol 1995Am J Resp Cell Mol Biol 1997Am J Resp Crit Care Med 1997, Am J Physiol 2000Protective 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 Clearance F
4、unctionsI. 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
5、 (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 animals 3 or 6 h after bact. injectionParameters: Bacterial counts in lung, liver, spleen & kidneyNumber of bacterial colonies in the lungKelbel et al. 1999Long-term li
6、pid-infusion in miceLeukocyte Invasion in a Model of Acute Lung Injury Impact of n-3 LipidsLPS*Crit Care Med 2007BALBroncho alveolar lavageLPSlipopolysaccharideEnteral n-3 lipids + anti-oxidants:N-3 Lipids & ARDSRCT of 146 critically ill patients acute lung injury and positive bronchoalveolar lavage
7、 for leukocytesDouble-blindedEnteral: N-3 Lipids vs. high fat dietGadek, Crit Care Med 1999;27:1409ARDS Enteral n-3 LipidsAdapted from: Gadek JE. et al., Crit Care Med 1999; 27:1409-20p = .011p = .016Do lipids modulate acute lung injury?Should we have faith in fat?Key Features of ARDS pulmonary hype
8、rtension VQ-mismatch / Shuntvasomotor dysfunction vascular leakagegas exchange secundary bacterial invasionQO2O2O2 leukocyte invasionCapillary sequestrationAlveolar invasionLipid emulsions are a mainstay of parenteral nutritionused in many ventilated patients with acute lung injuryImmunologic Effect
9、s of lipid emulsions in ARDSn-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 / bacterial killing?Endo/ExotoxinFocusBacterialtranslocationnosocomialPneumonia1. barrier dysfunc
10、tionGut2. 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 in endotoxic rats by n-3 lipidsL = SBOL-M = SBO+MCTFO-20 = L-M + FO(20%
11、)FO-40 = L-M + FO (40%)Pscheidl, E et alImpact of Fish Oil on LPS-induced Response in Volunteers8 volunteers 0.5 g/kg/d FO for 2 d8 volunteers no infusionLPS 2 ng/kg intravenousreadout: cytokines, hormones, RR, HF, temperature, Pluess T et al., Intensive Care Med. 2007; 33(5):789-97Fish Oil reduces
12、LPS-induced fever-response in volunteersEffect of SBO-based lipidsIncreased inflammatory responseReduced bacterial killing / clearanceIncreased primary / seconday organ damageMay translate into clinical effectsSIRSCARSBiphasic reaction of leukocytes in septic patientsHyperHypoEffective ResponseMayer
13、, 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 controlsNutrition:Parenteral nutrition over 10
14、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 Acad Dermatol 1998Intensive Care M
15、ed 2003Impact of Sepsis and Infusion of Lipid Emulsions on Free Fatty Acids*5-Lipoxygenase Metabolism in PMN* availability of free fatty acid (AA / EPA)* Eicosapentaenoic acid is the preferred substrateDesign: controlled, randomised studySetting:Intensive Care UnitPatients: 21 septic shock patients,
16、 6 healthy controlsNutrition:Parenteral nutrition over 5 days,total lipid intake 0.5 g/kg b.w./d Groups:1) Control: LCT 10% 2) FO 10%Parameters:FFA, CytokinesMayer, K et alMayer 2003, Am J Resp Crit Care MedMayer, Curr Opin Clin Nutr 2006Biochemical BackgroundUse of RvE1 in a Colitis-ModelRead-out:
17、Letality, weight, histologyinflammatory genesMayer, Curr Opin Clin Nutr 2006Impact of n-3 Lipids on ImmunityCase History 07.11.2006Female patient, *1939, Arterial hypertension, Smoker, Multiple herniates disks lower backPresented with acute abdomenBowel sounds presentPainTender AbdomenCase History 0
18、7.11.2006CT thorax + abdomen Exsudative pancreatitis Lung edemaCase History 07.11.2006transferred to medical intensive care unitClinical CourseUpon improvement transfer to step-down unit 3 days laterAfter 2 days development of acute dyspnoeaLow blood pressureClinical CourseRe-Transfer to intensive c
19、are unitBeginning ARDSSevere necrotising pancreatitis (CT)Clinical CourseIntubationDifficult respiratory situation FiO2 0,7 - 1,0; PaO2 50 70 mm Hg; Acute renal failureMODSClinical CourseSeptic courseAddition of FO (0.2 g/kg) i.v. on top of TPN (LCT / MCT 0.7 g/kg)Difficult ventilation, high oxygen
20、(FiO2 = 100%, ARDS)Later: low grade enteral nutrition via gastric route installedClinical CourseSlow improvement of the patientImprovement of ARDSSucessful weaning and extubationDischarge of the patient to a rehabilitation facilitySecond casePatient, male, *14.12.1961Travel to Italy a week before ad
21、mittancePresented with fever and cough to another hospitalClinical courseIntubation 01.07.2007Development of ARDSDifficult ventilation situationTransfer to our facility 02.07.2007Clinical course 02.07.2007PaO2/Fi02 = 60 mmHg, further detoriationInstallation of ECMO-therapyReceived diagnosis of legio
22、nella pneumonia due to positive urine test in other hospitalAddition of FO on top of TPN and ENClinical course 07.2007Gradual improvement with therapyWeaning from ECMOWeaning from ventilationDischarge to rehabilitation centerConclusion: Sepsis + n-3 lipidsBeneficial actions of n-3 FA containing lipi
23、d emulsions in models of acute lung injury and sepsisImproved organ function / integrityImproved bacterial killingImproved outcome due to n-3 FA containing diets in patients with acute lung injury and sepsisPossible benefits of n-3 containing lipid emulsions in septic patientsThank you for your attention结束结束
