Sepsis pp 425-442 | Cite as

N-Acetylcysteine in Sepsis

  • C. Spies
  • K. Reinhart
Part of the Update in Intensive Care and Emergency Medicine book series (UICM, volume 18)


Sepsis, septic shock and multiple organ dysfunction syndrome are characterized by progressive inadequate tissue perfusion and maldistribution of blood flow [1]. Endothelium-derived relaxing factor is considered to be important in maintaining nutrive blood flow [2]. Increased oxygen radicals known to be generated in large amounts during endotoxic shock and sepsis [3–8] inactivate nitric oxide or 5-nitrocysteine, which account for the vasodilator action of endothelium-derived relaxing factor [9–12]. A constitutive nitric oxide synthase is present in endothelial cells [9], certain neurons [3, 14], endocardium [15], myocardium [16] and platelets [17, 18].


Nitric Oxide Septic Shock Multiple Organ Dysfunction Syndrome Adult Respiratory Distress Syndrome Septic Shock Patient 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Members of the American College of Chest Physicians/Society of Critical Care Medicine, Consensus Conference Committee (1992) American College of Chest Physicians/ Society of Critical Care Medicine Consensus Conference: definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med 20:864–874CrossRefGoogle Scholar
  2. 2.
    Sun D, Messina EJ, Koller et al (1992) Endothelium-dependent dilation to L-arginine in isolated rat skeletal muscle arterioles. Am J Physiol 262:H1211–1216PubMedGoogle Scholar
  3. 3.
    Takeda Y, Shimada Y, Okada T et al (1986) Lipid peroxidation in experimental septic rats. Crit Care Med 14:719–723PubMedCrossRefGoogle Scholar
  4. 4.
    Weiss SJ (1989) Tissue destruction by neutrophils. NEJM 320:365–375PubMedCrossRefGoogle Scholar
  5. 5.
    Flohe L, Giertz H (1987) Endotoxins, arachodonic acid and superoxide formation. Rev Infect Dis 9:553–561CrossRefGoogle Scholar
  6. 6.
    Byrne K, Schneider A, Carey D et al (1989) Enhanced rate of superoxide anion generation among circulating neutrophils following pseudomonas aeruginosa sepsis in the pig. Circ Shock 27:330–334Google Scholar
  7. 7.
    Keen RR, Stella L, Flanigan P et al (1991) Differential detection of plasma hydroperoxides in sepsis. Crit Care Med 19:1114–1119PubMedCrossRefGoogle Scholar
  8. 8.
    Brigham KL (1991) Oxygen radicals — an important mediator of sepsis and septic shock. Klin Wochenschr 69:1004–1008PubMedCrossRefGoogle Scholar
  9. 9.
    Palmer RMJ, Ferrige AG, Moncada S (1987) Nitric oxide release accounts for the biological activity of endothelial-derived relaxing factor. Nature 327:524–526PubMedCrossRefGoogle Scholar
  10. 10.
    Ignarro LJ, Byrns RE, Buga GM et al (1987) Endothelium-derived relaxing factor from pulmonary artery and vein possesses pharmacologic and chemical properties identical to those of nitric oxide radical. Circ Res 61:866–879PubMedGoogle Scholar
  11. 11.
    Myers PR, Minor RL Jr, Guerra R Jr et al (1990) Vasorelaxant properties of the endothelium-derived relaxing factor more closely resemble S-nitrosocysteine than nitric oxide. Nature 345:161–163PubMedCrossRefGoogle Scholar
  12. 12.
    Gryglewski RJ, Palmer RM, Moncada S (1986) Superoxide anion is involved in the breakdown of endothelium-derived vascular relaxing factor. Nature 320:454–456PubMedCrossRefGoogle Scholar
  13. 13.
    Garthwaite J, Charles SL, Chess-Williams R (1988) Endothelium-derived relaxing factor release on activation of NMDA receptors suggests role as intracellular messenger in the brain. Nature 336:385–388PubMedCrossRefGoogle Scholar
  14. 14.
    Bredt DS, Hwang PM, Glatt CE et al (1991) Cloned and expressed nitric oxide synthase structurally resembles cytochrom P-450 reductase. Nature 351:714–718PubMedCrossRefGoogle Scholar
  15. 15.
    Schulz R, Smith JA, Lewis MJ et al (1991) Nitric oxide synthase in cultured endocardial cells of the pig, Br J Pharmacol 104:21–24PubMedGoogle Scholar
  16. 16.
    Schulz R, Nava E, Moncada S (1992) Induction and potential biological relevance of a Ca2+-independent nitric oxide synthase in the myocardium. Br J Pharmacol 105:575–580PubMedGoogle Scholar
  17. 17.
    Radomski MW, Palmer RMJ, Moncada S (1990) Characterization of the L-arginine: nitric oxide pathway in human platelets. Br J Pharmacol 101:325–328PubMedGoogle Scholar
  18. 18.
    Radomski MW, Palmer RMJ, Moncada S (1987) Comparative pharmacology of endothelium-derived relaxing factor, nitric oxide and prostacyclin in platelets. Br J Pharmacol 92:181–187PubMedGoogle Scholar
  19. 19.
    Chin JH, Azhar S, Hoffmann BB (1992) Inactivation of endothelium derived relaxing factor by oxidized lipoproteins. J Clin Invest 89:10–18PubMedCrossRefGoogle Scholar
  20. 20.
    Pacht ER, Timerman AP, Lykens MG et al (1991) Deficiency of alveolar fluid glutathione in patients with sepsis and the adult respiratory distress syndrome. Chest 100:1397–1403PubMedCrossRefGoogle Scholar
  21. 21.
    Ishii Y, Partridge CA, DelVecchio PJ et al (1992) Tumor necrosis factor alpha-mediated decrease in glutathione increases the sensitivity of pulmonary vascular endothelial cell to H2O2. J Clin Invest 89:794–802PubMedCrossRefGoogle Scholar
  22. 22.
    Westenberger U, Thanner S, Ruf HH et al (1990) Formation of free radicals and nitric oxide derivative of hemoglobin in rats during shock syndrome. Free Radic Res Commun 11:167–178PubMedCrossRefGoogle Scholar
  23. 23.
    Sugino K, Dohl K, Yamada K et al (1987) The role of lipid peroxidation in endotoxin induced hepatic damage and the protective effects of antioxidants. Surgery 101:746–752PubMedGoogle Scholar
  24. 24.
    Kirkpatrick CJ, Klosterhalfen B, Hauptmann S (1992) The role of the endothelium in multiple organ failure. In: Vincent J-L (ed) Yearbook of intensive care and emergency medicine. Springer, Berlin Heidelberg New York, pp 14–25Google Scholar
  25. 25.
    Onda M, Toba M, Andoh T et al (1986) Ultrastructural studies of experimental endotoxin shock in the liver and spleen. Therapeutic of low-dose heparin on reticuloendothelial disturbances. Circ Shock 18:11–19PubMedGoogle Scholar
  26. 26.
    Palmer RMJ, Bridge L, Foxwell NA et al (1992) The role of nitirc oxide in endothelial cell damage and its inhibition by glucocorticoids. Br J Pharmacol 105:11–12PubMedGoogle Scholar
  27. 27.
    Rees DD, Cellek S, Palmer RMJ et al (1990) Dexamethasone prevents the induction by endotoxin of a nitric oxide synthase and the associated effects on the vascular tone: an insight into endotoxin shock. Biochem Biophys Res Commun 173:541–547PubMedCrossRefGoogle Scholar
  28. 28.
    Busse R, Mulsch A (1990) Induction of nitric oxide synthase by cytokines in vascular smooth muscle, FEBS Lett 275:87–90PubMedCrossRefGoogle Scholar
  29. 29.
    Fleming I, Gray GA, Schott C et al (1991) Inducible but not constitutive production of nitric oxide by vascular smooth muscle cells. Eur J Pharmacol 200:375–376PubMedCrossRefGoogle Scholar
  30. 30.
    Vallance P, Palmer RMJ, Moncada S (1992) The role of induction of nitric oxide synthesis in the altered response of jugular veins from endotoxaemic rats. Br J Pharmacol 106:459–463PubMedGoogle Scholar
  31. 31.
    Moncada S, Palmer RMJ, Higgs EA (1991) Nitric oxide: Physiology, pathophysiology and pharmacology. Pharmacol Rev 43:109–142PubMedGoogle Scholar
  32. 32.
    Nussler AK, DiSilvio M, Billar TR et al (1992) Stimulation of the nitirc oxide synthase pathway in human hepatocytes by cytokines and endotoxin. J Exp Med 176:261–264PubMedCrossRefGoogle Scholar
  33. 33.
    Hibbs JB Jr, Vavrin Z, Taintor RR (1987) L-arginine is required for expression of the activated macrophage effector mechanism causing selective metabolic inhibition in target cells. J Immunol 138:550–565PubMedGoogle Scholar
  34. 34.
    Hibbs JB Jr, Taintor RR, Vavrin Z et al (1988) Nitric oxide: a cytotoxic activated macrophage effector molecule. Biochem Biophys Res Commun 157:87–94PubMedCrossRefGoogle Scholar
  35. 35.
    McCall T, Boughton-Smith NK, Palmer RMJ et al (1989) Synthesis of nitric oxide from L-arginine by neutrophils. Biochem J 261:293–296PubMedGoogle Scholar
  36. 36.
    Rimele TJ, Sturm RJ, Adams LM et al (1988) Interaction of neutrophils with vascular smooth muscle: identification of a neutrophil-derived relaxing factor. J Pharmacol Exp Ther 245:102–111PubMedGoogle Scholar
  37. 37.
    Adams LB, Hibbs JB Jr, Tainter RR et al (1990) Microbiostatic effect of murine macrophages for Toxoplasma gondii: role of synthesis of inorganic nitrogen oxides from L-arginine. J Immunol 144:2725–2729PubMedGoogle Scholar
  38. 38.
    Liew FY, Millott S, Parkinson C et al (1990) Macrophage killing of Leishmania parasite in vivo is mediated by nitric oxide from L-arginine. J Immunol 144:4794–4797PubMedGoogle Scholar
  39. 39.
    Denis M (1991) Tumor necrosis factor and granulocyte macrophage-colony stimulating factor stimulate human macrophages to restrict growth of virulent Mycobacterium avium and to kill avirulent M. avium. Killing effector mechanism depends on the generation of reactive nitrogen intermediates. J Leukoc Biol 48:380–387Google Scholar
  40. 40.
    Vallance P, Moncada S (1993) Role of endogenous nitric oxide in septic shock. New Horizons 1:77–86PubMedGoogle Scholar
  41. 41.
    Paterson IS, Klausner JM, Goldman G et al (1989) Pulmonary edema after aneurysm surgery is modified by mannitol. Ann Surg 210:796–801PubMedGoogle Scholar
  42. 42.
    Schiller HJ, Reilly P, Bulkley GB (1993) Antiooxidant therapy. Crit Care Med 21:S92–S102PubMedCrossRefGoogle Scholar
  43. 43.
    McCord JM (1985) Oxygen-free radicals in postischemic tissue injury. NEJM 312:159–163PubMedCrossRefGoogle Scholar
  44. 44.
    Goldhaber JI, Weiss JN (1992) Oxygen free radicals and cardiac reperfusion abnormalities. Hypertension 20:118–127PubMedGoogle Scholar
  45. 45.
    Ambrosio G, Santoro G, Tritto I et al (1992) Effects of ischemia and reperfusion on cardiac tolerance to oxdative stress. Am J Physiol 262(31):H23–H30PubMedGoogle Scholar
  46. 46.
    Holman RG, Maier RV (1988) Superoxide production by neutrophils in a model of adult respiratory distress syndrome. Arch Surg 123:1491–1495PubMedCrossRefGoogle Scholar
  47. 47.
    Nathan CF, Root RK (1977) Hydrogen peroxide release from mouse peritoneal macrophages. J Exp Med 146:1648–1653PubMedCrossRefGoogle Scholar
  48. 48.
    Makino R, Tanaka T, Iizuka T et al (1986) Stoichometric conversion of oxygen to Superoxide anion during the respiratory burst in neutrophils. J Biol Chem 261:11444–11447PubMedGoogle Scholar
  49. 49.
    Marshall PJ, Lands WEM (1986) In vitro formation of activators for prostaglandin synthesis by neutrophils and macrophages from humans and guinea pigs. J Lab Clin Med 108:525–530PubMedGoogle Scholar
  50. 50.
    Turner JJO, Rice-Evans CA, Davies MJ et al (1991) The formation of free radicals by cardiac myocytes under oxidative stress and the effects of electron-donating drugs. Biochem J 277:833–837PubMedGoogle Scholar
  51. 51.
    Youn Y-K, Lalonde C, Demling R (1991) Use of antioxidant therapy in shock and trauma. Circ Shock 35:245–249PubMedGoogle Scholar
  52. 52.
    Tuchschmidt J, Fried J, Astiz M et al (1992) Elevation of cardiac output and oxygen delivery improves outcome in sptic shock. Chest 102:16–20CrossRefGoogle Scholar
  53. 53.
    Hayes MA, Yau EHS, Timmins AC et al (1993) Response of critically ill patients to treatment aimed at achieving supranormal oxygen delivery and consumption. Relationship to outcome. Chest 103:886–895Google Scholar
  54. 54.
    Shoemaker WC (1993) A stitch in time saves lives. Chest 103:663–664PubMedCrossRefGoogle Scholar
  55. 55.
    Shoemaker WC, Appel PL, Kram HB et al (1988) Prospective trial of supranormal values of survivors as therapeutic goals in high risk surgical patients. Chest 94:1176–1186PubMedCrossRefGoogle Scholar
  56. 56.
    Gutierrez G, Palizas F, Doglio G, Wainsztein N et al (1992) Gastric intramucosal pH as a therapeutic index of tissue oxygenation in critically ill patients. Lancet 339:195–199PubMedCrossRefGoogle Scholar
  57. 57.
    Fink MP (1993) Adequacy of gut oxygenation in endotoxemia and sepsis. Crit Care Med 21:S4–S8PubMedCrossRefGoogle Scholar
  58. 58.
    Arndt H, Kubes P, Granger DN (1991) Involvement of neutrophils in ischemia-reperfusion injury of the small intestine. Klin Wochenschr 69:1056–1060PubMedCrossRefGoogle Scholar
  59. 59.
    Siems W, Kowalewski J, Werner A et al (1989) Radical formation in the rat small intestine during and following ischemia. Free Radic Res Commun 7:347–353PubMedCrossRefGoogle Scholar
  60. 60.
    Fiddian-Green RG, Baker S (1987) Predictive value of the stomach wall pH for complications after cardiac operations: comparison with other monitoring. Crit Care Med 5:153–156CrossRefGoogle Scholar
  61. 61.
    Antonsson JB, Boyle CC, Kruithoff KL et al (1990) Validity of tonometric measures of gut intramural pH during endotoxemia and mesenteric occlusion in pigs. Am J Physiol 259:G519–G523PubMedGoogle Scholar
  62. 62.
    Grum CM, Fiddian-Green RG, Pittenger GL et al (1984) Adequacy of tissue oxygenation in intact dog intestine. J Appl Physiol 56(4): 1065–1069PubMedGoogle Scholar
  63. 63.
    Doglio GR, Pusajo FJ, Egurrola MA et al (1991) Comparison between gastric intramucosal pH and pulmonary artery oxygen transport measurement on the intensive care unit. Crit Care Med 19:1037–1040PubMedCrossRefGoogle Scholar
  64. 64.
    Kunimoto F, Morita T, Fujita T (1987) Inhibition of lipid peroxidation improves survival rate of endotoxemic rats. Circ Shock 21:15–22PubMedGoogle Scholar
  65. 65.
    Broner CW, Shenep JL, Stidham GL et al (1988) Effect of scavengers of oxygenderived free radicals on mortality in endotoxin-challenged mice. Crit Care Med 16:848–854PubMedCrossRefGoogle Scholar
  66. 66.
    Morgan RA, Manning PB, Coran AG et al (1988) Oxygen free radical during live E. coli septic shock in the dog. Circ Shock 25:319–323Google Scholar
  67. 67.
    Schneider J, Friderichs E, Heintze K et al (1990) Effects of the recombinant human superoxide dismutase on increased lung permeability and respiratory disorder in endotoxemic rats. Circ Shock 30:97–106PubMedGoogle Scholar
  68. 68.
    Powell RJ, Machiedo GW, Rush BJ et al (1991) Effect of oxygen-free radical scavengers on survival in sepsis. Am Surg 57:86–88PubMedGoogle Scholar
  69. 69.
    Peck MD, Alexander JW (1991) Survival in septic guinea pigs is influenced by vitamin E, but not by vitamin C in enteral diets. J Parenter Ent Nutr 15:433–436CrossRefGoogle Scholar
  70. 70.
    Peavy PL, Fairchild EJ (1986) Evidence for lipid peroxidation in endotoxin-poisened mice. Infect Immunol 52:613–616Google Scholar
  71. 71.
    McKechnie K, Furman BL, Parrat JR (1986) Modification by oxygen free radical scavengers of the metabolic and cardiovascular effects of endotoxin infusion in conscious rats. Circ Shock 19:429–439PubMedGoogle Scholar
  72. 72.
    Brackett DJ, Lerner MR, Wilson MF (1991) Dimethyl sulfoxide antagonizes hypotensive, metabolic, and pathologic responses induced by endotoxin. Circ Shock 33:156–163PubMedGoogle Scholar
  73. 73.
    Hamburger SA, McCay PB (1989) Endotoxin-induced mortality in rats is reduced by nitrones. Circ Shock 29:329–334PubMedGoogle Scholar
  74. 74.
    Novelli GP (1992) Oxygen radicals in experimental shock: effects of spin-trapping nitrones in ameliorating shock pathophysiology. Crit Care Med 20:499–507PubMedCrossRefGoogle Scholar
  75. 75.
    Progrebniak HW, Merino J et al (1992) Spin trap salvage from endotoxemia: the role of cytokine down-regulation. Surgery 112:130–139Google Scholar
  76. 76.
    Progrebniak HW, Matthews WA et al (1990) Reactive oxygen species can amplify macrophage tumor necrosis factor production. Surg Forum 16:101–103Google Scholar
  77. 77.
    Yasumoto K, Inada Y (1986) Effect of coenzyme Q10 on endotoxin shock in dogs. Crit Care Med 14:570–574PubMedCrossRefGoogle Scholar
  78. 78.
    Lelli JL, Drongowski RA, Gastman B et al (1993) Effects of coenzyme Q10 on the mediator cascade of sepsis. Circ Shock 39:178–187PubMedGoogle Scholar
  79. 79.
    Powell RJ, Machiedo GW, Rush BF et al (1991) Oxygen free radicals: effect on red cell deformability in sepsis. Crit Care Med 19:732–735PubMedCrossRefGoogle Scholar
  80. 80.
    Arvidsson S, Fält K, Merklund S et al (1985) Role of free oxygen radicals in the development of gastrointestinal mucosal damage in Escheria coli sepsis. Circ Shock 16:383–393PubMedGoogle Scholar
  81. 81.
    Koyama S, Kobayshi T, Kubo K et al (1992) Recombinant human superoxide dismutase attenuates endotoxin-induced lung injury in awake sheep. ARRD 145:1404–1409Google Scholar
  82. 82.
    Brigham KL, Meyrick B, Berry LC et al (1987) Antioxidants protect cultured bovine lung endothelial cells from injury by endotoxin. J Appl Physiol 63:840–850PubMedGoogle Scholar
  83. 83.
    Matsuda T, Eccleston CA, Rubinstein et al (1991) Antioxidants attenuate endotoxininduced microvascular leakage of macromolecules in vivo. J Appl Physiol 70:1483–1489PubMedCrossRefGoogle Scholar
  84. 84.
    Harris CA, Derbin KS, Hunte-McDonugh B (1991) Manganese superoxide dismutase is induced by IFN-γ and tumor necrosis factor or IL-1. J Immunol 147:149–154PubMedGoogle Scholar
  85. 85.
    Leff JA, Oppegard MA, Tereda LS et al (1991) Human serum catalase decreased endothelial cell injury from hydrogen peroxide. J Appl Physiol 71(5):1903–1906PubMedGoogle Scholar
  86. 86.
    Rushmore TH, Morton MR, Pickett CB (1991) The antioxidant responsive element. J Biol Chem 266:11623–11639Google Scholar
  87. 87.
    Aruoma OI, Halliwell B, Hoey BM et al (1989) The antioxidant action of N-acetylcysteine: its reaction with hydrogen peroxide, hydroxyl radical, superoxide, and hypochlorous acid. J Free Radicals Biol Med 6:593–597CrossRefGoogle Scholar
  88. 88.
    Bernard GR, Lucht WD, Niedermeyer ME et al (1984) Effect of N-acetylcysteine on the pulmonary response to endotoxin in the awake sheep and upon in vitro granulocyte function. J Clin Invest 73:1772–1784PubMedCrossRefGoogle Scholar
  89. 89.
    Harrison PM, Wendon JA, Gimson AES et al (1991) Improvement by acetylcysteine of hemodynamics and oxygen transport in fulminant hepatic failure. NEJM 324:1852–1857PubMedCrossRefGoogle Scholar
  90. 90.
    Suttorp N, Kästle S, Neuhof H (1991) Glutathione redox cycle is an important defense system of endothelial cells against chronic hyperoxia. Lung 196:203–214CrossRefGoogle Scholar
  91. 91.
    Meister A (1992) On the antioxidant effects of ascorbic acid and glutathione. Biochem Pharmacol 44:1905–1915PubMedCrossRefGoogle Scholar
  92. 92.
    Chow CK (1991) Vitamin E and oxidative stress. Free Radic Biol Med 11:215–232PubMedCrossRefGoogle Scholar
  93. 93.
    Rubanyi GM, Vanhoutte PM (1986) Superoxide anions and hyperoxia inactivate endothelium-derived relaxing factor. Am J Physiol 250:H822–H827PubMedGoogle Scholar
  94. 94.
    Packer M, Lee WH, Kessler PD et al (1987) Prevention and reversal of nitrate tolerance in patients with congestive heart failure. NEJM 317:799–807PubMedCrossRefGoogle Scholar
  95. 95.
    May DC, Popma JJ, Black WH et al (1987) In vivo induction and reversal of nitroglycerin tolerance in human coronary arteries. NEJM 317:805–809PubMedCrossRefGoogle Scholar
  96. 96.
    Henry PJ, Horowitz JD, Louis WJ (1989) Determinants of in vitro nitroglycerine tolerance induction and reversal: influence of dose regimen, nitrate-free period, and sulfhydryl supplementation. J Cardiovasc Pharmacol 14:31–37PubMedCrossRefGoogle Scholar
  97. 97.
    Patterson CE, Butler JA, Byrne FD et al (1985) Oxidant lung injury: interventions with sulfhydryl reagents. Lung 163:23–32PubMedCrossRefGoogle Scholar
  98. 98.
    Spies CD, Hannemann L, Reinhart K et al (1992) N-Acetylcysteine (NAC) prevents decreased oxygen consumption during hyperoxia. Anesthesiology 77:A105CrossRefGoogle Scholar
  99. 99.
    Clancy RM, Leszczynska-Piziak J, Abramson SB (1992) Nitric oxide, an endothelial cell relaxation factor inhibits neutrophil superoxide anion production via a direct action on the NADPH oxidase. J Clin Invest 90:1116–1121PubMedCrossRefGoogle Scholar
  100. 100.
    Bath PMW, Hassal DG, Gladwin A-M et al (1991) Nitric oxide and prostacyclin: divergence of inhibitory effects on monocyte chemotaxis and adhesion to endothelium in vitro. Arterioscler Thromb 11:254–260PubMedCrossRefGoogle Scholar
  101. 101.
    Meilion BT, Ignarro LJ, Ohlstein EH et al (1981) Evidence for the inhibitory role of guanosine 3′,5′monophosphate in ADP induced human platelet aggregation in the presence of nitric oxide and related vasodilators. Blood 57:946–955Google Scholar
  102. 102.
    Ignarro LJ, Kadowitz PJ (1985) The pharmacological and physiological role of cyclic GMP in vascular smooth muscle relaxation. Annu Rev Pharmacol Toxicol 24:171–191CrossRefGoogle Scholar
  103. 103.
    Schwartz CJ, Valente AJ, Sprague EA, Kelley JL, Nerem RM (1991) The pathogenesis of atherosclerosis: an overview. Clin Cardiol 14:1–16CrossRefGoogle Scholar
  104. 104.
    Schwartz CJ, Sprague EA (1992) Vascular endothelium and hemodynamic stress. Nutr Metab Cardiovasc Dis 2:99–100Google Scholar
  105. 105.
    Ku DN, Giddens DP, Zarins CK et al (1985) Pulsatile flow and atherosclerosis in the human carotid bifurcation. Positive correlation between plaque localization and low and oscillating shear stress. Arteriosclerosis 5:293–302Google Scholar
  106. 106.
    Asakura T, Karino T (1990) Flow patterns and spatial distribution of atherosclerotic lesions in human coronary arteries. Circ Res 66:1045–1066PubMedGoogle Scholar
  107. 107.
    Diamond SL, Eskin SG, McIntire LV (1989) Fluid flow stimulates tissue plasminogen activator secretion by cultured human endothelial cells. Science 243:1483–1485PubMedCrossRefGoogle Scholar
  108. 108.
    Frangos JA, Mclntire LV, Eskin SG et al (1985) Flow effects on prostacyclin production by cultured human endothelial cells. Science 227:1477–1479PubMedCrossRefGoogle Scholar
  109. 109.
    Grabowski EF, Jaffe EA, Weksler BB (1985) Prostacyclin production by cultured endothelial cell monolayers exposed to step increases in shear stress. J Lab Clin Med 105:36–45PubMedGoogle Scholar
  110. 110.
    Cayatte AJ, Schwartz CJ, Nerem RM, Rozek MM, Sprague EA (1989) Decreased adherence of platelets and monocytes to preendothelialized porous polyester mesh exposed to prolonged elevated shear stress. In: Norman J (ed) Cardiovascular science and technology: basic and applied: I. Oxymoron, Louisville, Kentucky, pp 57–59Google Scholar
  111. 111.
    Redl H, Dinges HP, Schlag G et al (1991) Expression of endothelial leukocyte adhesion molecule-1 in septic but not traumatic/hypovolemic shock in the baboon. Am J Pathol 139:461–466PubMedGoogle Scholar
  112. 112.
    Spies C, Reinhart K et al (1993) Influence of N-Acetylcysteine on O2 consumption and gastric intramucosal pH in septic patients. Crit Care Med 21:S183CrossRefGoogle Scholar
  113. 113.
    Bernard GR, Swindell BB, Meredith MJ et al (1989) Glutathione repletion by N-acetylcysteine (NAC) in patients with the adult respiratory distress syndrome. ARRD 139:A221Google Scholar
  114. 114.
    Fiddian-Green RG (1993) Associations between intramucosal acidosis in the gut and organ failure. Crit Care Med 21:S103–S107PubMedCrossRefGoogle Scholar
  115. 115.
    Mecher CE, Rackow EC, Astiz A et al (1990) Venous hypercarbia associated with severe sepsis and systemic hypoperfusion. Crit Care Med 18:585–589PubMedCrossRefGoogle Scholar
  116. 116.
    Bakker J, Vincent JL, Gris P et al (1992) Veno-arterial carbon dioxide gradient in human septic shock. Chest 101:509–515PubMedCrossRefGoogle Scholar
  117. 117.
    Parrillo JE, Parker MM, Natanson C et al (1990) Septic shock in humans. Advances in the understanding of pathogenesis, cardiovascular dysfunction and therapy. Ann Intern Med 113:227–242Google Scholar
  118. 118.
    Horowitz JD, Antman EM, Lorell BH et al (1983) Potentiation of the cardiovascular effects of nitroglycerin by N-acetylcysteine. Circulation 68:1247–1253PubMedCrossRefGoogle Scholar
  119. 119.
    Forman MB, Puett DW, Cates CU et al (1988) Glutathione redox pathway and reperfusion injury: effect of N-acetylcysteine of infarct size and ventricular function. Circulation 78:202–213PubMedCrossRefGoogle Scholar
  120. 120.
    Bolli R, Jeroudi MO, Patel BS et al (1989) Marked reduction of free radical generation and contractile dysfunction by antioxidant therapy begun at the time of reperfusion. Circ Res 65:607–622PubMedGoogle Scholar
  121. 121.
    Jepsen S, Herlevsen P, Knudsen P et al (1992) Antioxidant treatment with N-acetylcysteine during adult respiratory distress syndrome: a prospective, randomized, placebo-controlled study. Crit Care Med 20:918–923PubMedCrossRefGoogle Scholar
  122. 122.
    Meyrick B, Brigham KL (1983) Acute effects of Escherichia coli endotoxin on the pulmonary microcirculation of anesthetized sheep: structure-function relationships. Lab Invest 48:458–470PubMedGoogle Scholar
  123. 123.
    Esbenshade AM, Newman JH, Lams PM et al (1982) Respiratory failure after endotoxin infusion in sheep: lung mechanics and lung fluid balance. L Appl Physiol 53:967–976Google Scholar
  124. 124.
    Groeneveld ABJ, deHollander W, Straub J et al (1990) Effects of N-acetylcysteine and terbutaline treatment on hemodynamics and regional albumin extravasation in porchine septic shock. Circ Shock 30:185–205PubMedGoogle Scholar
  125. 125.
    Ghezzi P, Saccardo B, Bianchi M (1989) Role of reactive oxygen intermediates in the hepatotoxicity of endotoxin. Immunopharmacology 12:241–244CrossRefGoogle Scholar
  126. 126.
    Olson NC, Anderson DL, Grizzle MK (1987) Dimethyl thiourea attenuate endotoxininduced acute respiratory failure in pigs. J Appl Physiol 63:2426–2432PubMedGoogle Scholar
  127. 127.
    Tate RM, Van Benthuysen KM, Shasby DM et al (1981) Dimethylurea, a hydroxyl radical scavenger, blocks oxygen radical-induced acute edematous lung injury in an isolated perfused lung. ARRD 123:243 (abstract)Google Scholar
  128. 128.
    Miller JS, Cormwell DG (1978) the role of cryoprotective agents as hydroxyl scavengers. Cryobiology 15:585–588PubMedCrossRefGoogle Scholar
  129. 129.
    Ashwood-Smith MJ (1975) Current concepts concerning radioprotective and cryoprotective properties of dimethylsulfoxide in cellular systems. Ann NY Acad Sci 243:246–256PubMedCrossRefGoogle Scholar
  130. 130.
    Harbrecht BG, Billiar TR, Stadler J et al (1992) Nitric oxide synthesis serves to reduce hepatic damage during acute murine endotoxemia. Crit Care Med 20:1568–1574PubMedCrossRefGoogle Scholar
  131. 131.
    Billiar RT, Curran RD, Harbrecht BG et al (1990) Modulation of nitrogen oxide synthesis in vivo: NG-methyl-L-arginine inhibits endotoxin-induced nitrite/nitrate biosynthesis while promoting hepatic damage. J Leukoc Biol 48:565–569PubMedGoogle Scholar
  132. 132.
    Hutcheson IR, Whittle BJR, Boughton-Smith NK (1990) Role of nitric oxide in maintaining vascular integrity in endotoxin-induced acute intestinal damage in the rat. Br J Pharmacol 101:815–820PubMedGoogle Scholar
  133. 133.
    Wright C, Rees D, Moncada S (1992) Protective and pathological roles of nitric oxide in endotoxin shock. Cardiovasc Res 26:48–57PubMedCrossRefGoogle Scholar
  134. 134.
    Hollenberg SM, Cunnion RE, Parrillo JE (1992) Effect of septic on vascular smooth muscle: in vitro studies using rat aortic rings. Crit Care Med 20:993–998PubMedCrossRefGoogle Scholar
  135. 135.
    Stadler J, Billiar TR, Curran RD et al (1991) Effect of exogenous and endogenous nitric oxide on mitochondrial respiration of rat hepatocytes. Am J Physiol 260:C910–916PubMedGoogle Scholar
  136. 136.
    Pellat C, Henry Y, Drapier J-C (1990) IFN-gamma-activated macrophages: detection by electron paramagnetic resonance of complexes between L-arginine derived nitric oxide and non-heme iron proteins. Biochem Biophys Res Commun 166:119–125PubMedCrossRefGoogle Scholar
  137. 137.
    Beckman JS, Beckman TW, Chen J et al (1990) Apparent hydroxyl radical production by peroxynitrate: implications for endothelial injury from nitric oxide and superoxide. Proc Natl Acad Sci USA 87:1620–1624PubMedCrossRefGoogle Scholar
  138. 138.
    Hogg N, Darley-Usmar D, Wilson MT et al (1992) Production of hydroxyl radicals from the simultaneous generation of superoxide and nitric oxide. Biochem J 281:419–424PubMedGoogle Scholar
  139. 139.
    Radi R, Beckman JS, Bush KM et al (1991) Peroxynitrate oxidation of sulfhydryls: the cytotoxic potential of superoxide and nitric oxide. J Biol Chem 266:4244–4250PubMedGoogle Scholar
  140. 140.
    Boyd O, Bennett ED (1992) Is oxygen consumption an important clinical target? In: Vincent J-L (ed) Yearbook of intensive care and emergency medicine. Springer, Berlin Heidelberg New York, pp 310–324Google Scholar
  141. 141.
    Kilbourn RG, Jubran A, Gross SS et al (1990) Reversal of endotoxin-mediated shock by NG-methyl-L-arginine, an inhibitor of nitric oxide synthesis. Biochem Biophys Res Commun 172:1132–1138PubMedCrossRefGoogle Scholar
  142. 142.
    Ochoa JB, Ukdekwu AO, Billiar TR et al (1991) Nitrogen oxide levels in patients after trauma and during sepsis. Ann Surg 214:621–626PubMedCrossRefGoogle Scholar
  143. 143.
    Lübbe AS, Garrison RN, Cryer HM et al (1992) Endothelium-derived relaxing factor as a possible mediator of sepsis — induced arteriolar dilation in skeletal muscle. Am J Physiol 262:H880–H887PubMedGoogle Scholar
  144. 144.
    Nava E, Palmer RMJ, Moncada S (1991) Inhibition of nitric oxide synthesis in septic shock: how much is beneficial?. Lancet 338:1555–1557PubMedCrossRefGoogle Scholar
  145. 145.
    Petros A, Bennett D, Vallance P (1991) Effect of nitric oxide synthase inhibitors on hypotension in patients with septic shock. Lancet 338:1557–1558PubMedCrossRefGoogle Scholar
  146. 146.
    Meyer J, Traber LD, Nelson S et al (1992) Reversal of hyperdynamic response to continuous endotoxin administration by inhibition of NO synthesis. J Appl Physiol 73(1): 324–328PubMedGoogle Scholar
  147. 147.
    Vallance P, Leone A, Calver A et al (1992) Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure. Lancet 339:572–575PubMedCrossRefGoogle Scholar
  148. 148.
    Voerman HJ, Stehouwer CDA, van Kamp GJ et al (1992) Plasma endothelin levels are increased during septic shock. Crit Care Med 20:1097–1101PubMedCrossRefGoogle Scholar
  149. 149.
    Pittet J-F, Morel DR, Hemsen A et al (1991) Elevated plasma endothelin-1 concentrations are associated with the severity of illness in patients with sepsis. Ann Surg 213:261–264PubMedCrossRefGoogle Scholar
  150. 150.
    Freund H, Atamian S, Holroyde J et al (1979) Plasma amino acids as predictors of the severity and outcome of sepsis. Ann Surg 190:571–576PubMedCrossRefGoogle Scholar
  151. 151.
    Vente JP, von Meyenfeldt MF, van Eijk HMH et al (1989) Plasma amino acid profiles in sepsis and stress. Ann Surg 209:57–62PubMedCrossRefGoogle Scholar
  152. 152.
    Wang Q, Jacobs J, DeLeo J et al (1991) Nitric oxide hemoglobin in mice and rats in endotoxin shock. Life Sci 49:55–60CrossRefGoogle Scholar
  153. 153.
    Finkel MS, Oddis CV, Jacob TD et al (1992) Negative inotropic effects of cytokines on the heart mediated by nitric oxide. Science 257:387–389PubMedCrossRefGoogle Scholar
  154. 154.
    Smith REA, Palmer RMJ, Moncada S (1991) Coronary vasodilation induced by endotoxin in the rabbit isolated perfused heart is nitric oxide — dependent and inhibited by dexamethasone. Br J Pharmacol 104:5–6PubMedGoogle Scholar
  155. 155.
    Estrada C, Gomez C, Martin C et al (1992) Nitric oxide mediates tumor necrosis factor-α cytotoxicity in endothelial cells. Biochem Biophys Res Commun 186:475–482PubMedCrossRefGoogle Scholar
  156. 156.
    Cirino G, Cicala C, Sorrentino L et al (1991) Effect of bradykinin antagonist, NG-monomethyl-L-arginine and L-NG-nitro arginine on phospholipase A2 induced edema in rat paw. Gen Pharmacol 22:801–804PubMedCrossRefGoogle Scholar
  157. 157.
    Hughes SR, Williams TJ, Brain SD et al (1990) Evidence that endogenous nitric oxide modulates edema formation induced by substance P. Eur J Pharmacol 191:481–484PubMedCrossRefGoogle Scholar
  158. 158.
    Kroncke K-D, Kolb-Bachofen V, Berschick B et al (1991) Activated macrophages kill pancreatic syngeneic islet cells via arginine-dependent nitric oxide generation. Biochem Biophys Res Commun 175:752–758PubMedCrossRefGoogle Scholar
  159. 159.
    Bergmann L, Kroncke K-D, Suscheck C et al (1992) Cytotoxic action of IL-1b against pancreatic islet cells is mediated via nitric oxide formation and is inhibited by NG-monomethyl-L-arginine. FEBS Lett 299:103–106PubMedCrossRefGoogle Scholar
  160. 160.
    Salvemini D, Mollace V, Pistelli A et al (1992) Cultured astrocytoma cells generate a nitric oxide-like factor from endogenous L-arginine and glyceroltrinitrate: effect of E. coli lipopolysaccharide. Br J Pharmacol 106:931–936Google Scholar
  161. 161.
    Monig J, Asmus K-D, Forni LG et al (1987) Detection of thiyl radicals. Int Radiat Biol 52:589–602CrossRefGoogle Scholar
  162. 162.
    Saez G, Thornalley PJ, Hill HAO (1982) The production of free radicals during the autooxidation of cysteine and their effect on isolated rat hepatocytes. Biochim Biophys Acta 719:24–31PubMedCrossRefGoogle Scholar
  163. 163.
    Bihari D, Smithies M, Gimson A et al (1987) The effects of vasodilation with prostacyclin on oxygen delivery and uptake in critically ill patients. NEJM 317:397–403PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1994

Authors and Affiliations

  • C. Spies
  • K. Reinhart

There are no affiliations available

Personalised recommendations