Sepsis-induced myocardial dysfunction: Pathophysiology and management

Journal of Intensive Care

Volumn 4, Issue 1, 2016, Pages

  Kakihana, Yasuyuki ^a   Ito, Takashi ^a   Nakahara, Mayumi ^a   Yamaguchi, Keiji ^a   Yasuda, Tomotsugu ^a  

^a KAGOSHIMA UNIVERSITY   (Japan)

Author keywords

Damage associated molecular patterns; Immune system; Infection; Septic shock; Systemic inflammatory response syndrome

Indexed keywords

1 FLUORO 3 (2 NITRO 1 IMIDAZOLYL) 2 PROPANOL F 18; ADENYLATE CYCLASE; BACTERIAL TOXIN; CYCLIC AMP; DOBUTAMINE; HEART MUSCLE DEPRESSANT FACTOR; HIGH MOBILITY GROUP B1 PROTEIN; HISTONE; INTERLEUKIN 1BETA; LEVOSIMENDAN; NITRIC OXIDE; PATHOGEN ASSOCIATED MOLECULAR PATTERN; TROPONIN T; TUMOR NECROSIS FACTOR ALPHA;

ADRENERGIC STIMULATION; ANTIBIOTIC THERAPY; CARDIAC MUSCLE CELL; DIASTOLIC DYSFUNCTION; DISORDERS OF MITOCHONDRIAL FUNCTIONS; ENDOTHELIAL DYSFUNCTION; HEART EJECTION FRACTION; HEART FUNCTION; HEART LEFT VENTRICLE EJECTION FRACTION; HEART LEFT VENTRICLE ENDDIASTOLIC VOLUME; HEART OUTPUT; HEMORRHAGIC SHOCK; HYPOKINESIA; HYPOVOLEMIA; INTENSIVE CARE; ISCHEMIA; MEMBRANE PERMEABILITY; MYOCARDIAL DISEASE; PATHOPHYSIOLOGY; PRIORITY JOURNAL; PULMONARY HYPERTENSION; RESUSCITATION; REVIEW; SEPTIC SHOCK;

EID: 84991035135     PISSN: None     EISSN: 20520492     Source Type: Journal    
DOI: 10.1186/s40560-016-0148-1     Document Type: Review

References (105)

1. Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA, et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest. 1992;101:1644-55.
2. Annane D, Bellissant E, Cavaillon JM. Septic shock. Lancet. 2005;365:63-78.
3. Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell. 2006;124:783-801.
4. Russell JA, Boyd J, Nakada T, Thair S, Walley KR. Molecular mechanisms of sepsis. Contrib Microbiol. 2011;17:48-85.
5. Bianchi ME. DAMPs, PAMPs and alarmins: all we need to know about danger. J Leukoc Biol. 2007;81:1-5.
6. Akira S, Takeda K. Toll-like receptor signalling. Nat Rev Immunol. 2004;4:499-511.
7. Thomas JA, Haudek SB, Koroglu T, Tsen MF, Bryant DD, White DJ, et al. IRAK1 deletion disrupts cardiac Toll/IL-1 signaling and protects against contractile dysfunction. Am J Physiol Heart Circ Physiol. 2003;285:H597-606.
8. Adib-Conquy M, Cavaillon JM. Host inflammatory and anti-inflammatory response during sepsis. Pathol Biol (Paris). 2012;60:306-13.
9. Soriano FG, Lorigados CB, Pacher P, Szabó C. Effects of a potent peroxynitrite decomposition catalyst in murine models of endotoxemia and sepsis. Shock. 2011;35:560-6.
10. Torres-Dueñas D, Celes MR, Freitas A, Alves-Filho JC, Spiller F, Dal-Secco D, et al. Peroxynitrite mediates the failure of neutrophil migration in severe polymicrobial sepsis in mice. Br J Pharmacol. 2007;152:341-52.
11. Clowes Jr GH, Vucinic M, Weidner MG. Circulatory and metabolic alterations associated with survival or death in peritonitis: clinical analysis of 25 cases. Ann Surg. 1966;163:866-85.
12. MacLean LD, Mulligan WG, McLean AP, Duff JH. Patterns of septic shock in man-a detailed study of 56 patients. Ann Surg. 1967;166:543-62.
13. Wilson RF, Chiscano AD, Quadros E, Tarver M. Some observations on 132 patients with septic shock. Anesth Analg. 1967;46:751-63.
14. Abraham E, Shoemaker WC, Bland RD, Cobo JC. Sequential cardiorespiratory patterns in septic shock. Crit Care Med. 1983;11:799-803.
15. Wilson RF, Sarver EJ, LeBlanc PL. Factors affecting hemodynamics in clinical shock with sepsis. Ann Surg. 1971;174:939-43.
16. Bone RC. Gram-negative sepsis. Background, clinical features, and intervention. Chest. 1991;100:802-8.
17. Parker MM, Shelhamer JH, Bacharach SL, Green MV, Natanson C, Frederick TM, et al. Profound but reversible myocardial depression in patients with septic shock. Ann Intern Med. 1984;100:483-90.
18. Jardin F, Fourme T, Page B, Loubières Y, Vieillard-Baron A, Beauchet A, et al. Persistent preload defect in severe sepsis despite fluid loading: a longitudinal echocardiographic study in patients with septic shock. Chest. 1999;116:1354-9.
19. Morelli A, De Castro S, Teboul JL, Singer M, Rocco M, Conti G, et al. Effects of levosimendan on systemic and regional hemodynamics in septic myocardial depression. Intensive Care Med. 2005;31:638-44.
20. Poelaert J, Declerck C, Vogelaers D, Colardyn F, Visser CA. Left ventricular systolic and diastolic function in septic shock. Intensive Care Med. 1997;23:553-60.
21. Charpentier J, Luyt CE, Fulla Y, Vinsonneau C, Cariou A, Grabar S, et al. Brain natriuretic peptide: a marker of myocardial dysfunction and prognosis during severe sepsis. Crit Care Med. 2004;32:660-5.
22. Parrillo JE, Parker MM, Natanson C, Suffredini AF, Danner RL, Cunnion RE, et al. Septic shock in humans. Advances in the understanding of pathogenesis, cardiovascular dysfunction, and therapy. Ann Intern Med. 1990;113:227-42.
23. Chagnon F, Bentourkia M, Lecomte R, Lessard M, Lesur O. Endotoxininduced heart dysfunction in rats: assessment of myocardial perfusion and ermeability and the role of fluid resuscitation. Crit Care Med. 2006;34:127-33.
24. Yu P, Boughner DR, Sibbald WJ, Keys J, Dunmore J, Martin CM. Myocardial collagen changes and edema in rats with hyperdynamic sepsis. Crit Care Med. 1997;25:657-62.
25. Cohen RI, Shapir Y, Chen L, Scharf SM. Right ventricular overload causes the decrease in cardiac output after nitric oxide synthesis inhibition in endotoxemia. Crit Care Med. 1998;26:738-47.
26. Moore TD, Frenneaux MP, Sas R, Atherton JJ, Morris-Thurgood JA, Smith ER, et al. Ventricular interaction and external constraint account for decreased stroke work during volume loading in CHF. Am J Physiol Heart Circ Physiol. 2001;281:H2385-91.
27. Cotran RS, Pober JS. Cytokine-endothelial interactions in inflammation, immunity, and vascular injury. J Am Soc Nephrol. 1990;1:225-35.
28. Hotchkiss RS, Karl IE. Reevaluation of the role of cellular hypoxia and bioenergetic failure in sepsis. JAMA. 1992;267:1503-10.
29. Hinshaw LB, Archer LT, Spitzer JJ, Black MR, Peyton MD, Greenfield LJ. Effects of coronary hypotension and endotoxin on myocardial performance. Am J Physiol. 1974;227:1051-7.
30. Coalson JJ, Hinshaw LB, Guenter CA, Berrell EL, Greenfield LJ. Pathophysiologic responses of the subhuman primate in experimental septic shock. Lab Invest. 1975;32:561-9.
31. Schlag G, Redl H, Hallström S, Radmore K, Davies J. Hyperdynamic sepsis in baboons: I. Aspects of hemodynamics. Circ Shock. 1991;34:311-8.
32. Cunnion RE, Schaer GL, Parker MM, Natanson C, Parrillo JE. The coronary circulation in human septic shock. Circulation. 1986;73:637-44.
33. Dhainaut JF, Huyghebaert MF, Monsallier JF, Lefevre G, Dall'Ava-Santucci J, Brunet F, et al. Coronary hemodynamics and myocardial metabolism of lactate, free fatty acids, glucose, and ketones in patients with septic shock. Circulation. 1987;75:533-41.
34. Hinshaw LB. Sepsis/septic shock: participation of the microcirculation: an abbreviated review. Crit Care Med. 1996;24:1072-8.
35. Groeneveld AB, van Lambalgen AA, van den Bos GC, Bronsveld W, Nauta JJ, Thijs LG. Maldistribution of heterogeneous coronary blood flow during canine endotoxin shock. Cardiovasc Res. 1991;25:80-8.
36. Madorin WS, Rui T, Sugimoto N, Handa O, Cepinskas G, Kvietys PR. Cardiac myocytes activated by septic plasma promote neutrophil transendothelial migration: role of platelet-activating factor and the chemokines LIX and KC. Circ Res. 2004;94:944-51.
37. ver Elst KM, Spapen HD, Nguyen DN, Garbar C, Huyghens LP, Gorus FK. Cardiac troponins I and T are biological markers of left ventricular dysfunction in septic shock. Clin Chem. 2000;46:650-7.
38. Wu AH. Increased troponin in patients with sepsis and septic shock: myocardial necrosis or reversible myocardial depression? Intensive Care Med. 2001;27:959-61.
39. Hotchkiss RS, Rust RS, Dence CS, Wasserman TH, Song SK, Hwang DR, et al. Evaluation of the role of cellular hypoxia in sepsis by the hypoxic marker [18F]fluoromisonidazole. Am J Physiol. 1991;261:R965-72.
40. Herbertson MJ, Werner HA, Russell JA, Iversen K, Walley KR. Myocardial oxygen extraction ratio is decreased during endotoxemia in pigs. J Appl Physiol (1985). 1995;79:479-86.
41. Powell RJ, Machiedo GW, Rush Jr BF, Dikdan G. Oxygen free radicals: effect on red cell deformability in sepsis. Crit Care Med. 1991;19:732-5.
42. Solomon MA, Correa R, Alexander HR, Koev LA, Cobb JP, Kim DK, et al. Myocardial energy metabolism and morphology in a canine model of sepsis. Am J Physiol. 1994;266:H757-68.
43. Van Lambalgen AA, van Kraats AA, Mulder MF, Teerlink T, van den Bos GC. High-energy phosphates in heart, liver, kidney, and skeletal muscle of endotoxemic rats. Am J Physiol. 1994;266:H1581-7.
44. Levy RJ, Piel DA, Acton PD, Zhou R, Ferrari VA, Karp JS, et al. Evidence of myocardial hibernation in the septic heart. Crit Care Med. 2005;33:2752-6.
45. Wiggers CJ. Myocardial depression in shock; a survey of cardiodynamic studies. Am Heart J. 1947;33:633-50.
46. Lefer AM, Martin J. Origin of myocardial depressant factor in shock. Am J Physiol. 1970;218:1423-7.
47. Parrillo JE, Burch C, Shelhamer JH, Parker MM, Natanson C, Schuette W. A circulating myocardial depressant substance in humans with septic shock. Septic shock patients with a reduced ejection fraction have a circulating factor that depresses in vitro myocardial cell performance. J Clin Invest. 1985;76:1539-53.
48. Hallström S, Koidl B, Müller U, Werdan K, Schlag G. A cardiodepressant factor isolated from blood blocks Ca2+ current in cardiomyocytes. Am J Physiol. 1991;260:H869-76.
49. Hoffmann JN, Werdan K, Hartl WH, Jochum M, Faist E, Inthorn D. Hemofiltrate from patients with severe sepsis and depressed left ventricular contractility contains cardiotoxic compounds. Shock. 1999;12:174-80.
50. Pathan N, Sandiford C, Harding SE, Levin M. Characterization of a myocardial depressant factor in meningococcal septicemia. Crit Care Med. 2002;30:2191-8.
51. Kumar A, Thota V, Dee L, Olson J, Uretz E, Parrillo JE. Tumor necrosis factor alpha and interleukin 1beta are responsible for in vitro myocardial cell depression induced by human septic shock serum. J Exp Med. 1996;183:949-58.
52. Vincent JL, Bakker J, Marécaux G, Schandene L, Kahn RJ, Dupont E. Administration of anti-TNF antibody improves left ventricular function in septic shock patients. Results of a pilot study. Chest. 1992;101:810-5.
53. Abraham E, Wunderink R, Silverman H, Perl TM, Nasraway S, Levy H, et al. Efficacy and safety of monoclonal antibody to human tumor necrosis factor alpha in patients with sepsis syndrome. A randomized, controlled, doubleblind, multicenter clinical trial. TNF-alpha MAb Sepsis Study Group. JAMA. 1995;273:934-41.
54. Natanson C, Eichenholz PW, Danner RL, Eichacker PQ, Hoffman WD, Kuo GC, et al. Endotoxin and tumor necrosis factor challenges in dogs simulate the cardiovascular profile of human septic shock. J Exp Med. 1989;169:823-32.
55. Schulz R, Nava E, Moncada S. Induction and potential biological relevance of a Ca(2+)-independent nitric oxide synthase in the myocardium. Br J Pharmacol. 1992;105:575-80.
56. Finkel MS, Oddis CV, Jacob TD, Watkins SC, Hattler BG, Simmons RL. Negative inotropic effects of cytokines on the heart mediated by nitric oxide. Science. 1992;257:387-9.
57. Loppnow H, Werdan K, Reuter G, Flad HD. The interleukin-1 and interleukin-1 converting enzyme families in the cardiovascular system. Eur Cytokine Netw. 1998;9:675-80.
58. Kelly RA, Balligand JL, Smith TW. Nitric oxide and cardiac function. Circ Res. 1996;79:363-80.
59. Singal PK, Khaper N, Palace V, Kumar D. The role of oxidative stress in the genesis of heart disease. Cardiovasc Res. 1998;40:426-32.
60. Preiser JC, Zhang H, Vray B, Hrabak A, Vincent JL. Time course of inducible nitric oxide synthase activity following endotoxin administration in dogs. Nitric Oxide. 2001;5:208-11.
61. Khadour FH, Panas D, Ferdinandy P, Schulze C, Csont T, Lalu MM, et al. Enhanced NO and superoxide generation in dysfunctional hearts from endotoxemic rats. Am J Physiol Heart Circ Physiol. 2002;283:H1108-15.
62. Ichinose F, Buys ES, Neilan TG, Furutani EM, Morgan JG, Jassal DS, et al. Cardiomyocyte-specific overexpression of nitric oxide synthase 3 prevents myocardial dysfunction in murine models of septic shock. Circ Res. 2007;100:130-9.
63. Kumar A, Brar R, Wang P, Dee L, Skorupa G, Khadour F, Schulz R, et al. Role of nitric oxide and cGMP in human septic serum-induced depression of cardiac myocyte contractility. Am J Physiol. 1999;276:R265-76.
64. Kirov MY, Evgenov OV, Evgenov NV, Egorina EM, Sovershaev MA, Sveinbjørnsson B, et al. Infusion of methylene blue in human septic shock: a pilot, randomized, controlled study. Crit Care Med. 2001;29:1860-7.
65. Ichinose F, Hataishi R, Wu JC, Kawai N, Rodrigues AC, Mallari C, et al. A selective inducible NOS dimerization inhibitor prevents systemic, cardiac, and pulmonary hemodynamic dysfunction in endotoxemic mice. Am J Physiol Heart Circ Physiol. 2003;285:H2524-30.
66. Bougaki M, Searles RJ, Kida K, Yu J, Buys ES, Ichinose F. Nos3 protects against systemic inflammation and myocardial dysfunction in murine polymicrobial sepsis. Shock. 2010;34:281-90.
67. Dawson D, Lygate CA, Zhang MH, Hulbert K, Neubauer S, Casadei B. nNOS gene deletion exacerbates pathological left ventricular remodeling and functional deterioration after myocardial infarction. Circulation. 2005;112:3729-37.
68. Kleinbongard P, Schulz R, Rassaf T, Lauer T, Dejam A, Jax T, et al. Red blood cells express a functional endothelial nitric oxide synthase. Blood. 2006;107:2943-51.
69. Brealey D, Brand M, Hargreaves I, Heales S, Land J, Smolenski R, et al. Association between mitochondrial dysfunction and severity and outcome of septic shock. Lancet. 2002;360:219-23.
70. Suliman HB, Welty-Wolf KE, Carraway M, Tatro L, Piantadosi CA. Lipopolysaccharide induces oxidative cardiac mitochondrial damage and biogenesis. Cardiovasc Res. 2004;64:279-88.
71. Levy RJ, Vijayasarathy C, Raj NR, Avadhani NG, Deutschman CS. Competitive and noncompetitive inhibition of myocardial cytochrome C oxidase in sepsis. Shock. 2004;21:110-4.
72. Trumbeckaite S, Opalka JR, Neuhof C, Zierz S, Gellerich FN. Different sensitivity of rabbit heart and skeletal muscle to endotoxin-induced impairment of mitochondrial function. Eur J Biochem. 2001;268:1422-9.
73. Gellerich FN, Trumbeckaite S, Hertel K, Zierz S, Müller-Werdan U, Werdan K, Redl H, et al. Impaired energy metabolism in hearts of septic baboons: diminished activities of complex I and complex II of the mitochondrial respiratory chain. Shock. 1999;11:336-41.
74. Kelm M, Schäfer S, Dahmann R, Dolu B, Perings S, Decking UK, et al. Nitric oxide induced contractile dysfunction is related to a reduction in myocardial energy generation. Cardiovasc Res. 1997;36:185-94.
75. Zell R, Geck P, Werdan K, Boekstegers P. TNF-alpha and IL-1 alpha inhibit both pyruvate dehydrogenase activity and mitochondrial function in cardiomyocytes: evidence for primary impairment of mitochondrial function. Mol Cell Biochem. 1997;177:61-7.
76. Larche J, Lancel S, Hassoun SM, Favory R, Decoster B, Marchetti P, et al. Inhibition of mitochondrial permeability transition prevents sepsis-induced myocardial dysfunction and mortality. J Am Coll Cardiol. 2006;48:377-85.
77. Zhang Q, Raoof M, Chen Y, Sumi Y, Sursal T, Junger W, et al. Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature. 2010;464:104-7.
78. Ghiringhelli F, Apetoh L, Tesniere A, Aymeric L, Ma Y, Ortiz C, et al. Activation of the NLRP3 inflammasome in dendritic cells induces IL-1betadependent adaptive immunity against tumors. Nat Med. 2009;15:1170-8.
79. Iyer SS, Pulskens WP, Sadler JJ, Butter LM, Teske GJ, Ulland TK, et al. Necrotic cells trigger a sterile inflammatory response through the Nlrp3 inflammasome. Proc Natl Acad Sci U S A. 2009;106:20388-93.
80. Codina R, Vanasse A, Kelekar A, Vezys V, Jemmerson R. Cytochrome cinduced lymphocyte death from the outside in: inhibition by serum leucine-rich alpha-2-glycoprotein-1. Apoptosis. 2010;15:139-52.
81. Pullerits R, Bokarewa M, Jonsson IM, Verdrengh M, Tarkowski A. Extracellular cytochrome c, a mitochondrial apoptosis-related protein, induces arthritis. Rheumatology (Oxford). 2005;44:32-9.
82. Hassoun SM, Marechal X, Montaigne D, Bouazza Y, Decoster B, Lancel S, et al. Prevention of endotoxin-induced sarcoplasmic reticulum calcium leak improves mitochondrial and myocardial dysfunction. Crit Care Med. 2008;36:2590-6.
83. Minamikawa T, Sriratana A, Williams DA, Bowser DN, Hill JS, Nagley P. Chloromethyl-X-rosamine (MitoTracker Red) photosensitises mitochondria and induces apoptosis in intact human cells. J Cell Sci. 1999;112:2419-30.
84. Knowlton AA, Chen L, Malik ZA. Heart failure and mitochondrial dysfunction: the role of mitochondrial fission/fusion abnormalities and new therapeutic strategies. J Cardiovasc Pharmacol. 2014;63:196-206.
85. Kalbitz M, Grailer JJ, Fattahi F, Jajou L, Herron TJ, Campbell KF, et al. Role of extracellular histones in the cardiomyopathy of sepsis. FASEB J. 2015;29:2185-93.
86. Kleine TJ, Gladfelter A, Lewis PN, Lewis SA. Histone-induced damage of a mammalian epithelium: the conductive effect. Am J Physiol. 1995;268:C1114-25.
87. Nakahara M, Ito T, Kawahara K, Yamamoto M, Nagasato T, Shrestha B, et al. Recombinant thrombomodulin protects mice against histone-induced lethal thromboembolism. PLoS One. 2013;8, e75961.
88. Alhamdi Y, Abrams ST, Cheng Z, Jing S, Su D, Liu Z, et al. Circulating histones are major mediators of cardiac injury in patients with sepsis. Crit Care Med. 2015;43:2094-103.
89. Zhang C, Mo M, Ding W, Liu W, Yan D, Deng J, et al. High-mobility group box 1 (HMGB1) impaired cardiac excitation-contraction coupling by enhancing the sarcoplasmic reticulum (SR) Ca(2+) leak through TLR4-ROS signaling in cardiomyocytes. J Mol Cell Cardiol. 2014;74:260-73.
90. Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001;345:1368-77.
91. http://www.survivingsepsis.org/bundles/Pages/default.aspx. Accessed 16 3 2015.
92. Romero-Bermejo FJ, Ruiz-Bailen M, Gil-Cebrian J, Huertos-Ranchal MJ. Sepsis-induced cardiomyopathy. Curr Cardiol Rev. 2011;7:163-83.
93. Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med. 2013;41:580-637.
94. Tang C, Liu MS. Initial externalization followed by internalization of betaadrenergic receptors in rat heart during sepsis. Am J Physiol. 1996;270:R254-63.
95. Shepherd RE, Lang CH, McDonough KH. Myocardial adrenergic responsiveness after lethal and nonlethal doses of endotoxin. Am J Physiol. 1987;252:H410-6.
96. Matsuda N, Hattori Y, Akaishi Y, Suzuki Y, Kemmotsu O, Gando S. Impairment of cardiac beta-adrenoceptor cellular signaling by decreased expression of G(s alpha) in septic rabbits. Anesthesiology. 2000;93:1465-73.
97. Böhm M, Kirchmayr R, Gierschik P, Erdmann E. Increase of myocardial inhibitory G-proteins in catecholamine-refractory septic shock or in septic multiorgan failure. Am J Med. 1995;98:183-6.
98. Wu LL, Yang SL, Yang RC, Hsu HK, Hsu C, Dong LW, et al. G protein and adenylate cyclase complex-mediated signal transduction in the rat heart during sepsis. Shock. 2003;19:533-7.
99. Barraud D, Faivre V, Damy T, Welschbillig S, Gayat E, Heymes C, et al. Levosimendan restores both systolic and diastolic cardiac performance in lipopolysaccharide-treated rabbits: comparison with dobutamine and milrinone. Crit Care Med. 2007;35:1376-82.
100. Suzuki T, Morisaki H, Serita R, et al. Infusion of beta-adrenergic blocker esmolol attenuates myocardial dysfunction in septic rats. Crit Care Med. 2005;33:2294-301.
101. Piper RD, Li FY, Myers ML, Sibbald WJ. Effects of isoproterenol on myocardial structure and function in septic rats. J Appl Physiol (1985). 1999;86:993-1001.
102. Hagiwara S, Iwasaka H, Maeda H, Noguchi T. Landiolol, an ultrashort-acting beta1-adrenoceptor antagonist, has protective effects in an LPS-induced systemic inflammation model. Shock. 2009;31:515-20.
103. Gore DC, Wolfe RR. Hemodynamic and metabolic effects of selective beta1 adrenergic blockade during sepsis. Surgery. 2006;139:686-94.
104. Schmittinger CA, Dünser MW, Haller M, Ulmer H, Luckner G, Torgersen C, et al. Combined milrinone and enteral metoprolol therapy in patients with septic myocardial depression. Crit Care. 2008;12:R99.
105. Ito T, Kawahara K, Okamoto K, Yamada S, Yasuda M, Imaizumi H, et al. Proteolytic cleavage of high mobility group box 1 protein by thrombinthrombomodulin complexes. Arterioscler Thromb Vasc Biol. 2008;28:1825-30.