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Factors associated with stroke or death after carotid endarterectomy in Northern New England.

1. M.W. Merx, MD;
2. C. Weber, MD

+Author Affiliations

1. 
   
   From the Department of Medicine (M.W.M.), Division of Cardiology, Pulmonary Diseases and Vascular Medicine and the Institute of Molecular Cardiovascular Research (IMCAR) at the University Hospital (C.W.), RWTH Aachen University, Aachen, Germany.

1. Correspondence to Marc W. Merx, MD, Medizinische Klinik I, Universitätsklinikum der RWTH Aachen, Pauwelstraße 30, 52057 Aachen, Germany (e-mailmmerx@ukaachen.de), or Christian Weber, MD, Institut für Kardiovaskuläre Molekularbiologie, Universitätsklinikum der RWTH Aachen, Pauwelstraße 30, 52057 Aachen, Germany (e-mail cweber@ukaachen.de).

Abstract

Sepsis is generally viewed as a disease aggravated by an inappropriate immune response encountered in the afflicted individual. As an important organ system frequently compromised by sepsis and always affected by septic shock, the cardiovascular system and its dysfunction during sepsis have been studied in clinical and basic research for more than 5 decades. Although a number of mediators and pathways have been shown to be associated with myocardial depression in sepsis, the precise cause remains unclear to date. There is currently no evidence supporting global ischemia as an underlying cause of myocardial dysfunction in sepsis; however, in septic patients with coexistent and possibly undiagnosed coronary artery disease, regional myocardial ischemia or infarction secondary to coronary artery disease may certainly occur.

A circulating myocardial depressant factor in septic shock has long been proposed, and potential candidates for a myocardial depressant factor include

• cytokines,
• prostanoids, and
• nitric oxide, among others.
• Endothelial activation and
• induction of the coagulatory system also contribute to the pathophysiology in sepsis.

Prompt and adequate antibiotic therapy accompanied by surgical removal of the infectious focus, if indicated and feasible, is the mainstay and also the only strictly causal line of therapy. In the presence of severe sepsis and septic shock, supportive treatment in addition to causal therapy is mandatory. The purpose of this review is to delineate some characteristics of septic myocardial dysfunction, to assess the most commonly cited and reported underlying mechanisms of cardiac dysfunction in sepsis, and to briefly outline current therapeutic strategies and possible future approaches.

Characteristics of Myocardial Dysfunction in Sepsis

Using portable radionuclide cineangiography, Calvin et al¹³ were the first to demonstrate myocardial dysfunction in adequately volume-resuscitated septic patients with decreased ejection fraction and increased end-diastolic volume index. Adding pulmonary artery catheters to serial radionuclide cineangiography, Parker and colleagues¹¹ extended these observations with the 2 major findings that (1) survivors of septic shock were characterized by increased end-diastolic volume index and decreased ejection fraction, whereas nonsurvivors typically maintained normal cardiac volumes, and (2) these acute changes in end-diastolic volume index and ejection fraction, although sustained for several days, were reversible. More recently, echocardiographic studies have demonstrated impaired left ventricular systolic and diastolic function in septic patients.^14–16 These human studies, in conjunction with experimental studies ranging from the cellular level¹⁷ to isolated heart studies^18,19 and to in vivo animal models,^20–22 have clearly established decreased contractility and impaired myocardial compliance as major factors that cause myocardial dysfunction in sepsis.

Notwithstanding the functional and structural differences between the left and right ventricle, similar functional alterations, as discussed above, have been observed for the right ventricle, which suggests that right ventricular dysfunction in sepsis closely parallels left ventricular dysfunction.^23–26 However, the relative contribution of the right ventricle to septic cardiomyopathy remains unknown.

Myocardial dysfunction in sepsis has also been analyzed with respect to its prognostic value. Parker et al,²⁷ reviewing septic patients on initial presentation and at 24 hours to determine prognostic indicators, found a heart rate of <106 bpm to be the only cardiac parameter on presentation that predicted a favorable outcome. At 24 hours after presentation, a systemic vascular resistance index >1529 dyne · s⁻¹ · cm⁻⁵ · m⁻², a heart rate <95 bpm or a reduction in heart rate >18 bpm, and a cardiac index >0.5 L · min⁻¹ · m⁻² suggested survival.²⁷ In a prospective study, Rhodes et al²⁸ demonstrated the feasibility of a dobutamine stress test for outcome stratification, with nonsurvivors being characterized by an attenuated inotropic response. The well-established biomarkers in myocardial ischemia and heart failure, cardiac troponin I and T, as well as B-type natriuretic peptide, have also been evaluated with regard to sepsis-associated myocardial dysfunction. Although B-type natriuretic peptide studies have delivered conflicting results in septic patients (for review, see Maeder et al²⁹), several small studies have reported a relationship between elevated cardiac troponin T and I and left ventricular dysfunction in sepsis, as assessed by echocardiographic ejection fraction^30–33 or pulmonary artery catheter–derived left ventricular stroke work index.³⁴ Cardiac troponin levels also correlated with the duration of hypotension³⁵ and the intensity of vasopressor therapy.³⁴In addition, increased sepsis severity, measured by global scores such as the Simplified Acute Physiology Score II (SAPS II) or the Acute Physiology And Chronic Health Evaluation II score (APACHE II), was associated with increased cardiac troponin levels,^31,33 as was poor short-term prognosis.^32,33,35,36 Despite the heterogeneity of study populations and type of troponin studied, the mentioned studies were univocal in concluding that elevated troponin levels in septic patients reflect higher disease severity, myocardial dysfunction, and worse prognosis. In a recent meta-analysis of 23 observational studies, Lim et al³⁷ found cardiac troponin levels to be increased in a large percentage of critically ill patients. Furthermore, in a subset of studies that permitted adjusted analysis and comprised 1706 patients, this troponin elevation was associated with an increased risk of death (odds ratio, 2.5; 95% CI, 1.9 to 3.4, P<0.001)³⁷; however, the underlying mechanisms clearly require further research.

Thus, it appears reasonable to recommend inclusion of cardiac troponins in the monitoring of patients with severe sepsis and septic shock to facilitate prognostic stratification and to increase alertness to the presence of cardiac dysfunction in individual patients. However, it remains to be shown whether risk stratification based on cardiac troponins can identify patients in whom aggressive therapeutic regimens might reap the greatest benefit and so translate into a survival benefit.

Mechanisms Underlying Myocardial Dysfunction in Sepsis

Cardiac depression during sepsis is probably multifactorial (Figure). Nevertheless, it is important to identify individual contributing factors and mechanisms to generate worthwhile therapeutic targets. As a consequence, a vast array of mechanisms, pathways, and disruptions in cellular homeostasis have been examined in septic myocardium.

View larger version:

Synopsis of potential underlying mechanisms in septic myocardial dysfunction. MDS indicates myocardial depressant substance.

Therapeutic Approaches: The Present and the Future

A detailed discussion of therapeutic options in septic patients would clearly be beyond the scope of this review, and readers are kindly referred to the multiple excellent reviews published on the subject (eg, Hotchkiss and Karl,² Annane et al,⁴ and Dellinger et al⁹⁷). Although a number of preventive measures, such as prophylactic antibiotics, maintenance of normoglycemia, selective digestive tract decontamination, vaccines, and intravenous immunoglobulin, have shown benefit in distinct patient populations, preventive strategies with a broader aim remain elusive. Once sepsis is manifest (see the Table for criteria), prompt and adequate antibiotic therapy accompanied by surgical removal of the infectious focus, if indicated and feasible, is the mainstay and also the only strictly causal line of therapy. In the presence of severe sepsis and septic shock, supportive treatment in addition to causal therapy is mandatory. Supportive therapy encompasses early and goal-directed fluid resuscitation,⁹ vasopressor and inotropic therapy, red blood cell transfusion, mechanical ventilation, and renal support when indicated. It is very likely beneficial to monitor cardiac performance in these patients. A wide array of techniques are available for this purpose, ranging from echocardiography to pulmonary catheters, thermodilution techniques, and pulse pressure analysis.⁹⁸ Because none of these techniques have demonstrated superiority, physicians should use the method with which they are most familiar. Whichever method is chosen, it should be applied frequently to tailor supportive therapy to the individual patient and to achieve the “gold standard” of early goal-directed therapy. In recent years, several attempts have been made to therapeutically address myocardial dysfunction in sepsis. Although the combination of norepinephrine as vasopressor and dobutamine as inotropic agent is probably the most frequently applied in septic shock, there is currently no evidence to recommend one catecholamine over the other.⁹⁷ In human endotoxemia, epinephrine has been demonstrated to inhibit proinflammatory pathways and coagulation activation, as well as to augment antiinflammatory pathways,^99,100 whereas no immunomodulatory or coagulant effects could be demonstrated for dobutamine in a similar setting.¹⁰¹ Isoproterenol has recently been applied successfully in a small group of patients with septic shock, no known history of CAD, and inappropriate mixed venous oxygen concentration despite correction of hypoxemia and anemia.¹⁰² In a cecal ligation and double-puncture model of sepsis, the β-blocker esmolol given continuously after sepsis induction improved myocardial oxygen utilization and attenuated myocardial dysfunction,¹⁰³ which suggests that therapeutic strategies proven in ischemic heart failure might also hold promise in septic cardiomyopathy. However, the optimal mode of β-receptor stimulation (or indeed inhibition) to limit myocardial dysfunction remains a wide-open field for inspired investigation.

Given the generally accepted view of sepsis as a disease largely propelled by an inappropriate immune response, numerous basic research and clinical trials have been undertaken to curb the lethal toll of sepsis through modulation of this uncontrolled immune response.^2,3 To date, activated protein C¹⁰⁴ and low-dose hydrocortisone¹⁰⁵ have emerged as the only inflammation-modulating substances that have been confirmed to be of benefit in patients with severe sepsis and septic shock. Over the past years, increasing evidence has accumulated that suggests that inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase, or statins, have therapeutic benefits independent of cholesterol lowering, termed “pleiotropic” effects. These have added a wide scope of potential targets for statin therapy that range from decreasing renal function loss¹⁰⁶ and lowering mortality in patients with diastolic heart failure¹⁰⁷ to prevention and treatment of stroke,¹⁰⁸ to name just a few. These pleiotropic effects include antiinflammatory and antioxidative properties, improvement of endothelial function, and increased NO bioavailability and thus might contribute to the benefit observed with statin therapy. Notably, these important immunomodulatory effects of statins have been demonstrated to be independent of lipid lowering¹⁰⁹ and appear to be mediated via interference with the synthesis of mevalonate metabolites (nonsteroidal isoprenoid products). Blockade of the mevalonate pathway has been shown to suppress T-cell responses,¹¹⁰ reduce expression of class II major histocompatibility complexes on antigen presenting cells,¹⁰⁹ and inhibit chemokine synthesis in peripheral blood mononuclear cells.¹¹¹ Furthermore, CD11b integrin expression and CD11b-dependent adhesion of monocytes have been found to be attenuated by the initiation of statin treatment in hypercholesterolemic patients.¹¹² In this context, Yoshida et al¹¹³ have reported that statins reduce the expression of both monocytic and endothelial adhesion molecules, eg, the integrin leukocyte function-associated antigen-1 (LFA-1), via an inhibition of Rho GTPases, in particular their membrane anchoring by geranylation. In addition, mechanisms for antiinflammatory actions of statins have been revealed that are not related to the isoprenoid metabolism. For instance, Weitz-Schmidt et al¹¹⁴ have identified that some statins act as direct antagonists of LFA-1 owing to their capacity to bind to the regulatory site in the LFA-1 i-domain. In addition to these multifaceted antiinflammatory effects, statins may interfere with activation of the coagulation cascade, as illustrated by the suppression of LPS-induced monocyte tissue factor in vitro.¹¹⁵ Beyond their immunomodulatory functions, statins have been shown to exert direct antichlamydial effects during pulmonary infection with Chlamydia pneumoniae in mice,¹¹⁶ and a recent report suggests the benefit of statins may also extend to viral pathogens.¹¹⁷

Given the strong impact of statins on inflammation, statins might represent a welcome enforcement in the battle against severe infectious diseases such as sepsis. Consequently, several investigators have evaluated the role of statins in the prevention and treatment of sepsis. In a retrospective analysis, Liappis et al¹¹⁸ demonstrated a reduced overall and attributable mortality in patients with bacteremia who were treated concomitantly with statins. Pretreatment with simvastatin has been shown to profoundly improve survival in a polymicrobial murine model of sepsis by preservation of cardiovascular function and inhibition of inflammatory alterations.¹⁹ Encouraged by these findings, the same model was used to successfully treat sepsis in a clinically feasible fashion, ie, treatment was initiated several hours after the onset of sepsis. With different statins (atorvastatin, pravastatin, and simvastatin) being effective, the therapeutic potential of statins in sepsis appears to be a class effect.²² Recently, Steiner et al¹¹⁹observed that pretreatment with simvastatin can suppress the inflammatory response induced by LPS in healthy human volunteers. Furthermore, in a prospective observational cohort study in patients with acute bacterial infections performed by Almog et al,¹²⁰previous treatment with statins was associated with a considerably reduced rate of severe sepsis and intensive care unit admissions. A total of 361 patients were enrolled in that study, and 82 of these patients had been treated with statins for at least 4 weeks before their admission. Severe sepsis developed in 19% of patients in the no-statin group compared with only 2.4% in patients who were taking statins. The intensive care unit admission rates were 12.2% for the no-statin group and 3.7% for the statin group. Because of the number of patients enrolled, the study was not powered to detect differences in mortality, although the large effect on sepsis rate and intensive care unit admission were at least suggestive. As the most recent development in this field, Hackam et al¹²¹ have produced an impressive observational study by initial evaluation of 141 487 cardiovascular patients, which resulted in a well-paired and homogenous study cohort of 69 168 patients after propensity-based matching. Drawing from this solid base, Hackam and coauthors were able to support the conclusion that statin therapy is associated with a considerably decreased rate of sepsis (hazard ratio, 0.81; 95% CI, 0.72 to 0.90), severe sepsis (hazard ratio, 0.83; 95% CI, 0.70 to 0.97), and fatal sepsis (hazard ratio, 0.75; 95% CI, 0.61 to 0.93). This protective effect prevailed at both high and low statin doses and for several clinically important subpopulations, such as diabetic and heart failure patients.

As has been suggested previously,¹²² statins might provide cumulative benefit by reducing mortality from cardiovascular and infectious diseases such as sepsis. However, statins may have detrimental effects in distinct subsets of patients. Therefore, caution should prevail, and the use of statins in patients with sepsis must be accompanied by meticulous monitoring of unexpected side effects and well-designed randomized, controlled clinical trials.

Beyond an apparent rationale for randomized trials on statins in sepsis, it is notable that the results with other immunomodulatory approaches in sepsis have yielded rather limited success. For instance, use of the anti-TNF antibody F(ab′)2 fragment afelimomab led to a significant but rather modest reduction in risk of death and to improved organ-failure scores in patients with severe sepsis and elevated IL-6 levels.¹²³ Moreover, a selective inhibitor of group IIA secretory phospholipase A2 failed to improve clinical outcome for patients with severe sepsis, with a negative trend most pronounced among patients with cardiovascular failure.¹²⁴ Hence, because none of the available strategies proven to be effective in sepsis are designed specifically to target myocardial dysfunction, one might conclude that strategies that preferentially address cardiac morbidity in sepsis may be a promising area for investigation. For instance, lipoteichoic acid, a major virulence factor in Gram-positive sepsis, causes cardiac depression by activating myocardial TNF-α synthesis via CD14 and induces coronary vascular disturbances by activating thromboxane 2 synthesis. It thus contributes to cardiac depression and may therefore be a worthwhile and cardiac-specific target.¹²⁵ The implications of intensified efforts in the search for successful novel approaches to the treatment of myocardial dysfunction in sepsis may be considerable with regard to improved patient care that results in reduced mortality. This is of major significance in view of the substantial economic consequences of increasing sepsis morbidity in an aging population.

REFERENCES

in Circulation.2007; 116: 793-802 doi: 10.1161/​CIRCULATIONAHA.106.678359

1. ↵
   Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA, Schein RMH, Sibbald WJ. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Chest. 1992; 101: 1644–1655.

   Abstract/FREE Full Text
2. ↵
   Hotchkiss RS, Karl IE. The pathophysiology and treatment of sepsis. N Engl J Med. 2003; 348: 138–150.

   CrossRefMedline
3. ↵
   Riedemann NC, Guo R, Ward PA. Novel strategies for the treatment of sepsis.Nat Med. 2003; 9: 517–524.

   CrossRefMedline
4. ↵
   Annane D, Bellissant E, Cavaillon JM. Septic shock. Lancet. 2005; 365: 63–78.

   CrossRefMedline
5. ↵
   Martin GS, Mannino DM, Eaton S, Moss M. The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med. 2003; 348: 1546–1554.

   CrossRefMedline
6. ↵
   Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med. 2001; 29: 1303–1310.

   CrossRefMedline
7. ↵
   Padkin A, Goldfrad C, Brady AR, Young D, Black N, Rowan K. Epidemiology of severe sepsis occurring in the first 24 hrs in intensive care units in England, Wales, and Northern Ireland. Crit Care Med. 2003; 31: 2332–2338.

   CrossRefMedline
8. ↵
   Waisbren BA. Bacteremia due to gram-negative bacilli other than the Salmonella: a clinical and therapeutic study. AMA Arch Intern Med. 1951; 88: 467–488.

   Medline
9. ↵
   Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B, Peterson E, Tomlanovich M; Early Goal-Directed Therapy Collaborative Group. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med.2001; 345: 1368–1377.

   CrossRefMedline
10. ↵
    Bone RC. Gram-negative sepsis: background, clinical features, and intervention.Chest. 1991; 100: 802–808.

    Abstract/FREE Full Text
11. ↵
    Parker MM, Shelhamer JH, Bacharach SL, Green MV, Natanson C, Frederick TM, Damske BA, Parrillo JE. Profound but reversible myocardial depression in patients with septic shock. Ann Intern Med. 1984; 100: 483–490.

    Abstract/FREE Full Text
12. ↵
    Parrillo JE, Parker MM, Natanson C, Suffredini AF, Danner RL, Cunnion RE, Ognibene FP. Septic shock in humans: advances in the understanding of pathogenesis, cardiovascular dysfunction, and therapy. Ann Intern Med. 1990; 113:227–242.

    Abstract/FREE Full Text
13. ↵
    Calvin JE, Driedger AA, Sibbald WJ. An assessment of myocardial function in human sepsis utilizing ECG gated cardiac scintigraphy. Chest. 1981; 80: 579–586.

    FREE Full Text
14. ↵
    Jafri SM, Lavine S, Field BE, Bahorozian MT, Carlson RW. Left ventricular diastolic function in sepsis. Crit Care Med. 1990; 18: 709–714.

    Medline
15. ↵
    Munt B, Jue J, Gin K, Fenwick J, Tweeddale M. Diastolic filling in human severe sepsis: an echocardiographic study. Crit Care Med. 1998; 26: 1829–1833.

    Medline
16. ↵
    Poelaert J, Declerck C, Vogelaers D, Colardyn F, Visser CA. Left ventricular systolic and diastolic function in septic shock. Intensive Care Med. 1997; 23: 553–560.

    CrossRefMedline
17. ↵
    Ren J, Ren BH, Sharma AC. Sepsis-induced depressed contractile function of isolated ventricular myocytes is due to altered calcium transient properties. Shock.2002; 18: 285–288.

    CrossRefMedline
18. ↵
    McDonough KH, Smith T, Patel K, Quinn M. Myocardial dysfunction in the septic rat heart: role of nitric oxide. Shock. 1998; 10: 371–376.

    Medline
19. ↵
    Merx MW, Liehn EA, Janssens U, Lütticken R, Schrader J, Hanrath P, Weber C. HMG-CoA reductase inhibitor simvastatin profoundly improves survival in a murine model of sepsis. Circulation. 2004; 109: 2560–2565.

    Abstract/FREE Full Text
20. ↵
    Natanson C, Fink MP, Ballantyne HK, Mac Vittie TJ, Conklin JJ, Parrillo JE. Gram-negative bacteremia produces both severe systolic and diastolic cardiac dysfunction in a canine model that simulates human septic shock. J Clin Invest.1986; 78: 259–270.

    Medline
21. ↵
    Stahl TJ, Alden PB, Ring WS, Madoff RC, Cerra FB. Sepsis-induced diastolic dysfunction in chronic canine peritonitis. Am J Physiol Heart Circ Physiol. 1990;258: H625–H633.

    Abstract/FREE Full Text
22. ↵
    Merx MW, Liehn EA, Graf J, van de Sandt A, Schaltenbrand M, Schrader J, Hanrath P, Weber C. Statin treatment after onset of sepsis in a murine model improves survival. Circulation. 2005; 112: 117–124.

    Abstract/FREE Full Text
23. ↵
    Vincent JL, Thirion M, Brimioulle S, Lejeune P, Kahn RJ. Thermodilution measurement of right ventricular ejection fraction with a modified pulmonary artery catheter. Intensive Care Med. 1986; 12: 33–38.

    CrossRefMedline
24. ↵
    Dhainaut JF, Brunet F, Monsaillier JF, Villemant D, Devaux JY, Konno M, De Gournay JM, Armaganidis A, Iotti G, Huyghebaert MF. Bedside evaluation of right ventricular performance using a rapid computerized thermodilution method. Crit Care Med. 1987; 15: 148–152.

    Medline
25. ↵
    Dhainaut JF, Lanore JJ, de Gournay JM, Huyghebaert MF, Brunet F, Villemant D, Monsallier JF. Right ventricular dysfunction in patients with septic shock.Intensive Care Med. 1988; 14: 488–491.

    Medline
26. ↵
    Parker MM, McCarthy KE, Ognibene FP, Parrillo JE. Right ventricular dysfunction and dilatation, similar to left ventricular changes, characterize the cardiac depression of septic shock in humans. Chest. 1990; 97: 126–131.

    Abstract/FREE Full Text
27. ↵
    Parker MM, Shelhamer JH, Natanson C, Alling DW, Parrillo JE. Serial cardiovascular variables in survivors and nonsurvivors of human septic shock: heart rate as an early predictor of prognosis. Crit Care Med. 1987; 15: 923–929.

    Medline
28. ↵
    Rhodes A, Lamb FJ, Malagon I, Newman PJ, Grounds RM, Bennett ED. A prospective study of the use of a dobutamine stress test to identify outcome in patients with sepsis, severe sepsis, or septic shock. Crit Care Med. 1999; 27: 2361–2366.

    CrossRefMedline
29. ↵
    Maeder M, Fehr T, Rickli H, Ammann P. Sepsis-associated myocardial dysfunction: diagnostic and prognostic impact of cardiac troponins and natriuretic peptides. Chest. 2006; 129: 1349–1366.

    Abstract/FREE Full Text
30. ↵
    Fernandes CJ, Akamine N, Knobel E. Cardiac troponin: a new serum marker of myocardial injury in sepsis. Intensive Care Med. 1999; 25: 1165–1168.

    CrossRefMedline
31. ↵
    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: 650–657.

    Abstract/FREE Full Text
32. ↵
    Ammann P, Fehr T, Minder EI, Gunter C, Bertel O. Elevation of troponin I in sepsis and septic shock. Intensive Care Med. 2001; 27: 965–969.

    CrossRefMedline
33. ↵
    Mehta NJ, Khan IA, Gupta V, Jani K, Gowda RM, Smith PR. Cardiac troponin I predicts myocardial dysfunction and adverse outcome in septic shock. Int J Cardiol.2004; 95: 13–17.

    CrossRefMedline
34. ↵
    Turner A, Tsamitros M, Bellomo R. Myocardial cell injury in septic shock. Crit Care Med. 1999; 27: 1775–1780.

    CrossRefMedline
35. ↵
    Arlati S, Brenna S, Prencipe L, Marocchi A, Casella GP, Lanzani M, Gandini C. Myocardial necrosis in ICU patients with acute non-cardiac disease: a prospective study. Intensive Care Med. 2000; 26: 31–37.

    CrossRefMedline
36. ↵
    Spies C, Haude V, Fitzner R, Schroder K, Overbeck M, Runkel N, Schaffartzik W. Serum cardiac troponin T as a prognostic marker in early sepsis. Chest. 1998;113: 1055–1063.

    Abstract/FREE Full Text
37. ↵
    Lim W, Qushmag I, Devereaux PJ, Heels-Ansdell D, Lauzier F, Ismaila AS, Crowther MA, Cook DJ. Elevated cardiac troponin measurements in critically ill patients. Arch Intern Med. 2006; 166: 2446–2454.

    Abstract/FREE Full Text
38. ↵
    Cunnion RE, Schaer GL, Parker MM, Natanson C, Parrillo JE. The coronary circulation in human septic shock. Circulation. 1986; 73: 637–644.

    Abstract/FREE Full Text
39. ↵
    Herbertson MJ, Werner HA, Russell JA, Iversen K, Walley KR. Myocardial oxygen extraction ratio is decreased during endotoxemia in pigs. J Appl Physiol.1995; 79: 479–486.

    Abstract/FREE Full Text
40. ↵
    Powell RJ, Machiedo GW, Rush BF, Dikdan G. Oxygen free radicals: effect on red cell deformability in sepsis. Crit Care Med. 1991; 19: 732–735.

    Medline
41. ↵
    Dhainaut JF, Huyghebaert MF, Monsallier JF, Lefevre G, Dall’Ava-Santucci J, Brunet F, Villemant D, Carli A, Raichvarg D. Coronary hemodynamics and myocardial metabolism of lactate, free fatty acids, glucose, and ketones in patients with septic shock. Circulation. 1987; 75: 533–541.

    Abstract/FREE Full Text
42. ↵
    Solomon MA, Correa R, Alexander HR, Koev LA, Cobb JP, Kim DK, Roberts WC, Quezado ZM, Scholz TD, Cunnion RE, Hoffman WD, Bacher J, Yatsiv I, Danner RL, Banks SM, Ferrans VJ, Balaban RS, Natanson C. Myocardial energy metabolism and morphology in a canine model of sepsis. Am J Physiol Heart Circ Physiol. 1994; 266: H757–H768.

    Abstract/FREE Full Text
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 Heart Circ Physiol. 1994; 266: H1581–H1587.

    Abstract/FREE Full Text
44. ↵
    Levy RJ, Piel DA, Acton PD, Zhou R, Ferrari VA, Karp JS, Deutschman CS. Evidence of myocardial hibernation in the septic heart. Crit Care Med. 2005; 33:2752–2756.

    CrossRefMedline
45. ↵
    Hinshaw LB. Sepsis/septic shock: participation of the microcirculation: an abbreviated review. Crit Care Med. 1996; 24: 1072–1078.

    CrossRefMedline
46. ↵
    Hoffmann R. Tissue Doppler echocardiography: already of clinical significance? Z Kardiol. 2002; 91: 677–684.

    CrossRefMedline
47. ↵
    Wiggers CJ. Myocardial depression in shock: a survey of cardiodynamic studies.Am Heart J. 1947; 33: 633–650.

    CrossRefMedline
48. ↵
    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: 1539–1553.

    Medline
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; 13: 174–180.
50. ↵
    Mink SN, Jacobs H, Duke K, Bose D, Cheng ZQ, Light RB. N,N′,N″-triacetylglucosamine, an inhibitor of lysozyme, prevents myocardial depression in Escherichia coli sepsis in dogs. Crit Care Med. 2004; 32: 184–193.

    Medline
51. ↵
    Suffredini AF, Fromm RE, Parker MM, Brenner M, Kovacs JA, Wesley RA, Parrillo JE. The cardiovascular response of normal humans to the administration of endotoxin. N Engl J Med. 1989; 321: 280–287.

    Medline
52. ↵
    Danner RL, Elin RJ, Hosseini JM, Wesley RA, Reilly JM, Parrillo JE. Endotoxemia in human septic shock. Chest. 1991; 99: 169–175.

    Abstract/FREE Full Text
53. ↵
    Reilly JM, Cunnion RE, Burch-Whitman C, Parker MM, Shelhamer JH, Parrillo JE. A circulating myocardial depressant substance is associated with cardiac dysfunction and peripheral hypoperfusion (lactic acidemia) in patients with septic shock. Chest. 1989; 95: 1072–1080.

    Abstract/FREE Full Text
54. ↵
    Sharma AC, Motew SJ, Farias S, Alden KJ, Bosmann HB, Law WR, Ferguson JL. Sepsis alters myocardial and plasma concentrations of endothelin and nitric oxide in rats. J Mol Cell Cardiol. 1997; 29: 1469–1477.

    CrossRefMedline
55. ↵
    Horton JW, Maass D, White J, Sanders B. Nitric oxide modulation of TNF-alpha-induced cardiac contractile dysfunction is concentration dependent. Am J Physiol Heart Circ Physiol. 2000; 278: H1955–H1965.

    Abstract/FREE Full Text
56. ↵
    Vincent JL, Bakker J, Marecaux 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: 810–815.

    Abstract/FREE Full Text
57. ↵
    Fisher CJ, Agosti JM, Opal SM, Lowry SF, Balk RA, Sadoff JC, Abraham E, Schein RM, Benjamin E; the Soluble TNF Receptor Sepsis Study Group. Treatment of septic shock with the tumor necrosis factor receptor:Fc fusion protein. N Engl J Med. 1996; 334: 1697–1702.

    CrossRefMedline
58. ↵
    Abraham E, Glauser MP, Butler T, Garbino J, Gelmont D, Laterre PF, Kudsk K, Bruining HA, Otto C, Tobin E, Zwingelstein C, Lesslauer W, Leighton A; Ro 45-2081 Study Group. p55 Tumor necrosis factor receptor fusion protein in the treatment of patients with severe sepsis and septic shock: a randomized controlled multicenter trial. JAMA. 1997; 277: 1531–1538.

    Abstract/FREE Full Text
59. ↵
    Abraham E, Anzueto A, Gutierrez G, Tessler S, San Pedro G, Wunderink R, Dal Nogare A, Nasraway S, Berman S, Cooney R, Levy H, Baughman R, Rumbak M, Light RB, Poole L, Allred R, Constant J, Pennington J, Porter S; NORASEPT II Study Group. Double-blind randomised controlled trial of monoclonal antibody to human tumour necrosis factor in treatment of septic shock. Lancet. 1998; 351: 929–933.

    Medline
60. ↵
    Francis SE, Holden H, Holt CM, Duff GW. Interleukin-1 in myocardium and coronary arteries of patients with dilated cardiomyopathy. J Mol Cell Cardiol. 1998;30: 215–223.

    CrossRefMedline
61. ↵
    Opal SM, Fisher CJ Jr, Dhainaut JF, Vincent JL, Brase R, Lowry SF, Sadoff JC, Slotman GJ, Levy H, Balk RA, Shelly MP, Pribble JP, LaBrecque JF, Lookabaugh J, Donovan H, Dubin H, Baughman R, Norman J, DeMaria E, Matzel K, Abraham E, Seneff M; Interleukin-1 Receptor Antagonist Sepsis Investigator Group. Confirmatory interleukin-1 receptor antagonist trial in severe sepsis: a phase III, randomized, double-blind, placebo-controlled, multicenter trial. Crit Care Med. 1997; 25: 1115–1124.

    CrossRefMedline
62. ↵
    Fisher CJ Jr, Dhainaut JF, Opal SM, Pribble JP, Balk RA, Slotman GJ, Iberti TJ, Rackow EC, Shapiro MJ, Greenman RL; Phase III rhIL-1ra Sepsis Syndrome Study Group. Recombinant human interleukin 1 receptor antagonist in the treatment of patients with sepsis syndrome: results from a randomized, double-blind, placebo-controlled trial. JAMA. 1994; 271: 1836–1843.

    Abstract/FREE Full Text
63. ↵
    Damas P, Ledoux D, Nys M, Vrindts Y, De Groote D, Franchimont P, Lamy M. Cytokine serum level during severe sepsis in human IL-6 as a marker of severity.Ann Surg. 1992; 215: 356–362.

    Medline
64. ↵
    Schulz R, Nava E, Moncada S. Induction and potential biological relevance of a Ca²⁺-independent nitric oxide synthase in the myocardium. Br J Pharmacol. 1992;105: 575–580.

    Medline
65. ↵
    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: 387–389.

    Abstract/FREE Full Text
66. ↵
    Liu SF, Newton R, Evans TW, Barnes PJ. Differential regulation of cyclo-oxygenase-1 and cyclo-oxygenase-2 gene expression by lipopolysaccharide treatment in vivo in the rat. Clin Sci (Lond). 1996; 90: 301–306.

    Medline
67. ↵
    Reines HD, Halushka PV, Cook JA, Wise WC, Rambo W. Plasma thromboxane concentrations are raised in patients dying with septic shock. Lancet. 1982; 2: 174–175.

    Medline
68. ↵
    Fletcher JR, Ramwell PW. Modification, by aspirin and indomethacin, of the haemodynamic and prostaglandin releasing effects of E. coli endotoxin in the dog.Br J Pharmacol. 1977; 61: 175–181.

    Medline
69. ↵
    Parratt JR, Sturgess RM. E. coli endotoxin shock in the cat; treatment with indomethacin. Br J Pharmacol. 1975; 53: 485–488.

    Medline
70. ↵
    Bernard GR, Wheeler AP, Russel JA, Schein R, Summer WR, Steinberg KP, Fulkerson WJ, Wright PE, Christmann BW, Dupont WD, Higgins SB, Swindell BB; The Ibuprofen in Sepsis Study Group. The effects of ibuprofen on the physiology and survival of patients with sepsis. N Engl J Med. 1997; 336: 912–918.

    CrossRefMedline
71. ↵
    Memis D, Karamanlioglu B, Turan A, Koyuncu O, Pamukcu Z. Effects of lornoxicam on the physiology of severe sepsis. Crit Care. 2004; 8: R474–R482.

    CrossRefMedline
72. ↵
    Tunctan B, Altug S, Uludag O, Demirkay B, Abacioglu N. Effects of cyclooxygenase inhibitors on nitric oxide production and survival in a mice model of sepsis. Pharmacol Res. 2003; 48: 37–48.

    Medline
73. ↵
    Reddy RC, Chen GH, Tateda K, Tsai WC, Phare SM, Mancuso P, Peters-Golden M, Standiford TJ. Selective inhibition of COX-2 improves early survival in murine endotoxemia but not in bacterial peritonitis. Am J Physiol Lung Cell Mol Physiol.2001; 281: L537–L543.

    Abstract/FREE Full Text
74. ↵
    Gupta A, Brahmbhatt S, Kapoor R, Loken L, Sharma AC. Chronic peritoneal sepsis: myocardial dysfunction, endothelin and signaling mechanisms. Front Biosci.2005; 10: 3183–3205.

    CrossRefMedline
75. ↵
    Shindo T, Kurihara H, Kurihara Y, Morita H, Yazaki Y. Upregulation of endothelin-1 and adrenomedullin gene expression in the mouse endotoxin shock model. J Cardiovasc Pharmacol. 1998; 31: S541–S544.

    CrossRefMedline
76. ↵
    Yang LL, Gros R, Kabir MG, Sadi A, Gotlieb AI, Husain M, Stewart DJ. Conditional cardiac overexpression of endothelin-1 induces inflammation and dilated cardiomyopathy in mice. Circulation. 2004; 109: 255–261.

    Abstract/FREE Full Text
77. ↵
    Konrad D, Oldner A, Rossi P, Wanecek M, Rudehill A, Weitzberg E. Differentiated and dose-related cardiovascular effects of a dual endothelin receptor antagonist in endotoxin shock. Crit Care Med. 2004; 32: 1192–1199.

    CrossRefMedline
78. ↵
    Schulz R, Rassaf T, Massion PB, Kelm M, Balligand JL. Recent advances in the understanding of the role of nitric oxide in cardiovascular homeostasis. Pharmacol Ther. 2005; 108: 225–256.

    CrossRefMedline
79. ↵
    Rassaf T, Poll LW, Brouzos P, Lauer T, Totzeck M, Kleinbongard P, Gharini P, Andersen K, Schulz R, Heusch G, Modder U, Kelm M. Positive effects of nitric oxide on left ventricular function in humans. Eur Heart J. 2006; 27: 1699–1705.

    Abstract/FREE Full Text
80. ↵
    Kelm M, Schafer S, Dahmann R, Dolu B, Perings S, Decking UK, Schrader J, Strauer BE. Nitric oxide induced contractile dysfunction is related to a reduction in myocardial energy generation. Cardiovasc Res. 1997; 36: 185–194.

    CrossRefMedline
81. ↵
    Merx MW, Godecke A, Flogel U, Schrader J. Oxygen supply and nitric oxide scavenging by myoglobin contribute to exercise endurance and cardiac function.FASEB J. 2005; 19: 1015–1017.

    Abstract/FREE Full Text
82. ↵
    Heusch G, Post H, Michel MC, Kelm M, Schulz R. Endogenous nitric oxide and myocardial adaptation to ischemia. Circ Res. 2000; 87: 146–152.

    Abstract/FREE Full Text
83. ↵
    Schulz R, Kelm M, Heusch G. Nitric oxide in myocardial ischemia/reperfusion injury. Cardiovasc Res. 2004; 61: 402–413.

    Abstract/FREE Full Text
84. ↵
    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: 208–211.

    CrossRefMedline
85. ↵
    Khadour FH, Panas D, Ferdinandy P, Schulze C, Csont T, Lalu MM, Wildhirt SM, Schulz R. Enhanced NO and superoxide generation in dysfunctional hearts from endotoxemic rats. Am J Physiol Heart Circ Physiol. 2002; 283: H1108–H1115.

    Abstract/FREE Full Text
86. ↵
    Pacher P, Beckman JS, Liaudet L. Nitric oxide and peroxynitrite in health and disease. Physiol Rev. 2007; 87: 315–424.

    Abstract/FREE Full Text
87. ↵
    Ullrich R, Scherrer-Crosbie M, Bloch KD, Ichinose F, Nakajima H, Picard MH, Zapol WM, Quezado ZM. Congenital deficiency of nitric oxide synthase 2 protects against endotoxin-induced myocardial dysfunction in mice. Circulation. 2000; 102:1440–1446.

    Abstract/FREE Full Text
88. ↵
    Hwang TL, Yeh CC. Hemodynamic and hepatic microcirculational changes in endotoxemic rats treated with different NOS inhibitors. Hepatogastroenterology.2003; 50: 188–191.

    Medline
89. ↵
    Kirov MY, Evgenov OV, Evgenov NV, Egorina EM, Sovershaev MA, Sveinbjornsson B, Nedashkovsky EV, Bjertanaes LJ. Infusion of methylene blue in human septic shock: a pilot, randomized, controlled study. Crit Care Med. 2001; 29:1860–1867.

    CrossRefMedline
90. ↵
    Ferdinandy P, Danial H, Ambrus I, Rothery RA, Schulz R. Peroxynitrite is a major contributor to cytokine-induced myocardial contractile failure. Circ Res. 2000;87: 241–247.

    Abstract/FREE Full Text
91. ↵
    Elfering SL, Sarkela TM, Giulivi C. Biochemistry of mitochondrial nitric-oxide synthase. J Biol Chem. 2002; 277: 38079–38086.

    Abstract/FREE Full Text
92. ↵
    Connelly L, Madhani M, Hobbs AJ. Resistance to endotoxic shock in endothelial nitric-oxide synthase (eNOS) knock-out mice: a pro-inflammatory role for eNOS-derived NO in vivo. J Biol Chem. 2005; 280: 10040–10046.

    Abstract/FREE Full Text
93. ↵
    Kleinbongard P, Schulz R, Rassaf T, Lauer T, Dejam A, Jax TW, Kumara I, Gharini P, Kabanova S, Ozuyaman B, Schnurch H-G, Gödecke A, Weber A-A, Robenek M, Robenek H, Bloch W, Rosen P, Kelm M. Red blood cells express a functional endothelial nitric oxide synthase. Blood. 2006; 107: 2943–2951.

    Abstract/FREE Full Text
94. ↵
    Raeburn CD, Calkins CM, Zimmerman MA, Song Y, Ao L, Banerjee A, Harken AH, Meng X. ICAM-1 and VCAM-1 mediate endotoxemic myocardial dysfunction independent of neutrophil accumulation. Am J Physiol Regul Integr Comp Physiol.2002; 283: R477–R486.

    Abstract/FREE Full Text
95. ↵
    Neviere R, Guery B, Mordon S, Zerimech F, Charre S, Wattel F, Chopin C. Inhaled NO reduces leukocyte-endothelial cell interactions and myocardial dysfunction in endotoxemic rats. Am J Physiol Heart Circ Physiol. 2000; 278:H1783–H1790.

    Abstract/FREE Full Text
96. ↵
    Raeburn CD, Calkins CM, Zimmerman MA, Song Y, Ao L, Banerjee A, Meng X, Harken AH. Vascular cell adhesion molecule-1 expression is obligatory for endotoxin-induced myocardial neutrophil accumulation and contractile dysfunction.Surgery. 2001; 130: 319–325.

    CrossRefMedline
97. ↵
    Dellinger RP, Carlet JM, Masur H, Gerlach H, Calandra T, Cohen J, Gea-Banacloche J, Keh D, Marshall JC, Parker MM, Ramsay G, Zimmerman JL, Vincent JL, Levy MM. Surviving sepsis campaign guidelines for management of severe sepsis and septic shock. Crit Care Med. 2004; 32: 858–873.

    CrossRefMedline
98. ↵
    Hollenberg SM, Ahrens TS, Annane D, Astiz ME, Chalfin DB, Dasta JF, Heard SO, Martin C, Napolitano LM, Susla GM, Totaro R, Vincent JL, Zanotti-Cavazzoni S. Practice parameters for hemodynamic support of sepsis in adult patients: 2004 update. Crit Care Med. 2004; 32: 1928–1948.

    CrossRefMedline
99. ↵
    van der Poll T, Coyle SM, Barbosa K, Braxton CC, Lowry SF. Epinephrine inhibits tumor necrosis factor-alpha and potentiates interleukin 10 production during human endotoxemia. J Clin Invest. 1996; 97: 713–719.

    Medline
100. ↵
     van der Poll T, Levi M, Dentener M, Jansen PM, Coyle SM, Braxton CC, Buurman WA, Hack CE, ten Cate JW, Lowry SF. Epinephrine exerts anticoagulant effects during human endotoxemia. J Exp Med. 1997; 185: 1143–1148.

     Abstract/FREE Full Text
101. ↵
     Lemaire L, de Kruif M, Giebelen IA, Levi M, van der Poll T, Heesen M. Dobutamine does not influence inflammatory pathways during human endotoxemia.Crit Care Med. 2006; 34: 1365–1371.

     CrossRefMedline
102. ↵
     Leone M, Boyadjiev I, Boulos E, Antonini F, Visintini P, Albanese J, Martin C. A reappraisal of isoproterenol in goal-directed therapy of septic shock. Shock. 2006;26: 353–357.

     CrossRefMedline
103. ↵
     Suzuki T, Morisaki H, Serita R, Yamamoto M, Kotake Y, Ishizaka A, Takeda J. Infusion of the beta-adrenergic blocker esmolol attenuates myocardial dysfunction in septic rats. Crit Care Med. 2005; 33: 2294–2301.

     CrossRefMedline
104. ↵
     Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, Lopez-Rodriguez A, Steingrub JS, Garber GE, Helterbrand JD, Ely EW, Fisher CJ Jr; Recombinant Human Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) Study Group. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med. 2001; 344: 699–709.

     CrossRefMedline
105. ↵
     Annane D. Corticosteroids for septic shock. Crit Care Med. 2001; 29: S117–S120.

     CrossRefMedline
106. ↵
     Tonelli M, Isles C, Craven T, Tonkin A, Pfeffer MA, Shepherd J, Sacks FM, Furberg C, Cobbe SM, Simes J, West M, Packard C, Curhan GC. Effect of pravastatin on rate of kidney function loss in people with or at risk for coronary disease. Circulation. 2005; 112: 171–178.

     Abstract/FREE Full Text
107. ↵
     Fukuta H, Sane DC, Brucks S, Little WC. Statin therapy may be associated with lower mortality in patients with diastolic heart failure: a preliminary report.Circulation. 2005; 112: 357–363.

     Abstract/FREE Full Text
108. ↵
     Zhang L, Zhang ZG, Ding GL, Jiang Q, Liu X, Meng H, Hozeska A, Zhang C, Li L, Morris D, Zhang RL, Lu M, Chopp M. Multitargeted effects of statin-enhanced thrombolytic therapy for stroke with recombinant human tissue-type plasminogen activator in the rat. Circulation. 2005; 112: 3486–3494.

     Abstract/FREE Full Text
109. ↵
     Kwak B, Mulhaupt F, Myit S, Mach F. Statins as a newly recognized type of immunomodulator. Nat Med. 2000; 6: 1399–1402.

     CrossRefMedline
110. ↵
     Kurakata S, Kada M, Shimada Y, Komai T, Nomoto K. Effects of different inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, pravastatin sodium and simvastatin, on sterol synthesis and immunological functions in human lymphocytes in vitro. Immunopharmacology. 1996; 34: 51–61.

     CrossRefMedline
111. ↵
     Romano M, Diomede L, Sironi M, Massimiliano L, Sottocorno M, Polentarutti N, Guglielmotti A, Albani D, Bruno A, Fruscella P, Salmona M, Vecchi A, Pinza M, Mantovani A. Inhibition of monocyte chemotactic protein-1 synthesis by statins. Lab Invest. 2000; 80: 1095–1100.

     Medline
112. ↵
     Weber C, Erl W, Weber KS, Weber PC. HMG-CoA reductase inhibitors decrease CD11b expression and CD11b-dependent adhesion of monocytes to endothelium and reduce increased adhesiveness of monocytes isolated from patients with hypercholesterolemia. J Am Coll Cardiol. 1997; 30: 1212–1217.

     Abstract
113. ↵
     Yoshida M, Sawada T, Ishii H, Gerszten RE, Rosenzweig A, Gimbrone MA Jr, Yasukochi Y, Numano F. HMG-CoA reductase inhibitor modulates monocyte-endothelial cell interaction under physiological flow conditions in vitro: involvement of Rho GTPase-dependent mechanism. Arterioscler Thromb Vasc Biol. 2001; 21:1165–1171.

     Abstract/FREE Full Text
114. ↵
     Weitz-Schmidt G, Welzenbach K, Brinkmann V, Kamata T, Kallen J, Bruns C, Cottens S, Takada Y, Hommel U. Statins selectively inhibit leukocyte function antigen-1 by binding to a novel regulatory integrin site. Nat Med. 2001; 7: 687–692.

     CrossRefMedline
115. ↵
     Colli S, Eligini S, Lalli M, Camera M, Paoletti R, Tremoli E. Vastatins inhibit tissue factor in cultured human macrophages: a novel mechanism of protection against atherothrombosis. Arterioscler Thromb Vasc Biol. 1997; 17: 265–272.

     Abstract/FREE Full Text
116. ↵
     Erkkila L, Jauhiainen M, Laitinen K, Haasio K, Tiirola T, Saikku P, Leinonen M. Effect of simvastatin, an established lipid-lowering drug, on pulmonary Chlamydia pneumoniae infection in mice. Antimicrob Agents Chemother. 2005; 49: 3959–3962.

     Abstract/FREE Full Text
117. ↵
     del Real G, Jimenez-Baranda S, Mira E, Lacalle RA, Lucas P, Gomez-Mouton C, Alegret M, Pena JM, Rodriguez-Zapata M, Alvarez-Mon M, Martinez A, Manes S. Statins inhibit HIV-1 infection by down-regulating Rho activity. J Exp Med. 2004;200: 541–547.

     Abstract/FREE Full Text
118. ↵
     Liappis AP, Kan VL, Rochester CG, Simon GL. The effect of statins on mortality in patients with bacteremia. Clin Infect Dis. 2001; 33: 1352–1357.

     Abstract/FREE Full Text
119. ↵
     Steiner S, Speidl WS, Pleiner J, Seidinger D, Zorn G, Kaun C, Wojta J, Huber K, Minar E, Wolzt M, Kopp CW. Simvastatin blunts endotoxin-induced tissue factor in vivo. Circulation. 2005; 111: 1841–1846.

     Abstract/FREE Full Text
120. ↵
     Almog Y, Shefer A, Novack V, Maimon N, Barski L, Eizinger M, Friger M, Zeller L, Danon A. Prior statin therapy is associated with a decreased rate of severe sepsis. Circulation. 2004; 110: 880–885.

     Abstract/FREE Full Text
121. ↵
     Hackam DG, Mamdani M, Li P, Redelmeier DA. Statins and sepsis in patients with cardiovascular disease: a population-based cohort analysis. Lancet. 2006; 367:413–418.

     CrossRefMedline
122. ↵
     Merx MW, Weber C. Statins: a preventive strike against sepsis in patients with cardiovascular disease? Lancet. 2006; 367: 372–373.

     CrossRefMedline
123. ↵
     Panacek EA, Marshall JC, Alberson TE, Johnson DH, Johnson S, MacArthur RD, Miller M, Barchuk WT, Fischkoff S, Kaul M, Teoh L, Van Meter L, Daum L, Lemeshow S, Hicklin G, Doig C. Efficacy and safety of the monoclonal anti-tumor necrosis factor antibody F(ab′)2 fragment afelimomab in patients with severe sepsis and elevated interleukin-6 levels. Crit Care Med. 2004; 32: 2173–2182.

     Medline
124. ↵
     Zeiher BG, Steingrub J, Laterre PF, Dmitrienko A, Fukiishi Y, Abraham E; EZZI Study Group. LY315920NA/S-5920, a selective inhibitor of group IIA secretory phospholipase A2, fails to improve clinical outcome for patients with severe sepsis.Crit Care Med. 2005; 33: 1741–1748.

     CrossRefMedline
125. ↵
     Grandel U, Hopf M, Buerke M, Hattar K, Heep M, Fink L, Bohle RM, Morath S, Hartung T, Pullamsetti S, Schermuly RT, Seeger W, Grimminger F, Sibelius U. Mechanisms of cardiac depression caused by lipoteichoic acids from Staphylococcus aureus in isolated rat hearts. Circulation. 2005; 112: 691–698.

     Abstract/FREE Full Text

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