Pathophysiology of Sepsis

【摘要】  Sepsis remains a critical problem with significant morbidity and mortality even in the modern era of critical care management. Multiple derangements exist in sepsis involving several different organs and systems, although controversies exist over their individual contribution to the disease process. Septic patients have substantial, life-threatening alterations in their coagulation system, and currently, there is an approved therapy with a component of the coagulation system (activated protein C) to treat patients with severe sepsis. Previously, it was believed that sepsis merely represented an exaggerated, hyperinflammatory response with patients dying from inflammation-induced organ injury. More recent data indicate that substantial heterogeneity exists in septic patients?? inflammatory response, with some appearing immuno-stimulated, whereas others appear suppressed. Cellular changes continue the theme of heterogeneity. Some cells work too well such as neutrophils that remain activated for an extended time. Other cellular changes become accelerated in a detrimental fashion including lymphocyte apoptosis. Metabolic changes are clearly present, requiring close and individualized monitoring. At this point in time, the literature richly illustrates that no single mediator/system/pathway/pathogen drives the pathophysiology of sepsis. This review will briefly discuss many of the important alterations that account for the pathophysiology of sepsis.
--------------------------------------------------------------------------------
Sepsis has been active as long as infectious agents have been present. Because bacteria predate humans, sepsis probably predates modern man.1 Despite intense efforts, sepsis remains a serious clinical problem, accounting for thousands of deaths every year. A recent review by Angus et al estimated the 1995 incidence of sepsis in the United States to be 751,000 cases, resulting in 215,000 deaths.2 The average cost per case of sepsis was $22,100 with total costs of $16.7 billion nationally. A more recent analysis of hospital records indicates that the total number of patients who are dying is actually increasing.3 This study also confirmed the work of Angus et al2 that the incidence of sepsis is increasing and projected to continue to grow as the population ages. These studies concluded that "severe sepsis is a common, expensive, and frequently fatal condition, with as many deaths annually as those from acute myocardial infarction."3 It is important to bear in mind that sepsis mortality is based on 28-day survival, in contrast to most mortality studies, which are based on 5-year survival. Therefore, in addition to its high lethality, sepsis also accounts for a significant number of years of life lost.
Two major consensus conferences have defined sepsis. The first, in 1992, put forth the concept of the Systemic Inflammatory Response Syndrome (SIRS), recognizing that lethally altered pathophysiology could be present without positive blood cultures.4 The SIRS criteria are listed in Table 1 . Some clarification concerning terminology will assist the reader in this review. Sepsis represents SIRS that has been induced by an infection.5 Severe sepsis is sepsis with dysfunction of a least one organ or organ system, and septic shock is severe sepsis with hypotension.
Table 1. Criteria for the Systemic Inflammatory Response Syndrome, Adapted from the American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference4
The 2001 International Sepsis Definitions Conference modified the model of SIRS and developed an expanded view of sepsis after revisiting the literature.6 This conference developed the concept of a staging system for sepsis based on four separate characteristics designated by the acronym PIRO. P stands for the predisposition, indicating pre-existing co-morbid conditions that would reduce survival. I is the insult or infection, which reflects the clinical knowledge that some pathogenic organisms are more lethal than others. R represents the response to the infectious challenge, including the development of SIRS. The last letter O stands for organ dysfunction and includes organ failure as well as the failure of a system such as the coagulation system.
What are the signs, symptoms, and causes of sepsis? Table 1 defines the changes that are observed in septic patients, but these alterations are extremely nonspecific, and an accurate diagnostic test for sepsis would be a welcome addition in the management of patients. The causes of sepsis are multifactorial but can include virtually any infectious organism. Recently, gram-positive infections have been documented to be more frequent than gram-negative infections.3 Although interactions between pathogens and the Toll-like receptors have been implicated in sepsis, mice genetically deficient in Toll-like receptors still succumb to true models of sepsis.7 Statements regarding the dominance of endotoxin in the pathogenesis of sepsis have not kept pace with the current published literature.
Opinions on the causes and potential therapies for sepsis have evolved over time, and this review will focus on some of the current thoughts concerning the basic mechanisms of the septic process. This brief review does not represent an exhaustive listing of all possibilities, and I hope no offense will be taken by those investigators whose area of work is not cited.

【关键词】  pathophysiology sepsis

Dysregulated Coagulation

Normal hemostasis exists as a finely tuned balance where the blood typically remains liquid to allow free flow within the vessels yet clots appropriately to control bleeding. Under normal conditions the clotting cascade is extremely complex.8 During inflammatory situations such as sepsis, significant alterations occur at multiple levels within both the coagulation system and the cells that regulate this system9 (Figure 1) . Septic patients frequently manifest disseminated intravascular coagulation (DIC) with consumption of platelets and prolongation of clotting times. In addition, the altered hemostasis allows blood to clot when it should not, clogging blood vessels and reducing blood flow. Because the liver produces fixed quantities of procoagulant factors, and the bone marrow releases a defined number of white blood cells into the circulation, local effects modulate the systemic coagulopathy. In other words, although the coagulopathy is systemic, the bleeding typically occurs in select sites, where dysfunctional vasculature provides the necessary environment for bleeding to occur at that site. The interaction between the clotting system, circulating white blood cells and platelets, and the endothelium adds another layer to an already multifaceted picture. Although several of these abnormalities have been documented in septic patients, the underlying cause of the coagulopathy almost certainly remains multifactorial.

Figure 1. Control of coagulation in normal and inflamed vasculature. Top panel: Normal function. Vascular injury, indicated on the lower portion of the blood vessel wall, initiates prothrombin (Pro) activation, which subsequently induces thrombin (T) formation. Prothrombin activation involves the formation of complexes between factor Va and factor Xa. Thrombin then binds to thrombomodulin (TM) on the luminal side of the endothelial cell wall, and the thrombin-TM complex converts protein C to APC. APC then binds to protein S (S) on endothelial cell surfaces. The complex composed of protein S and APC then converts factor Va into an inactive complex (VI). Protein S and APC also interact with the endothelial cell protein C receptor (EPCR). Bottom panel: After inflammation. During inflammation, specific mediators cause the disappearance of thrombomodulin from the endothelial cell surface. The endothelial cell leukocyte adhesion molecules P-selectin and E-selectin are synthesized and expressed on the surfaces of endothelial cells or platelets. Tissue factor (TF) is expressed on monocytes where it binds to factor VIIa. The TF-VIIa complex converts factor X to factor Xa, which then complexes with factor Va to generate thrombin from prothrombin. Very little APC is formed, and that which is formed does not function well because of low levels of protein S. Consequently, factor Va is not activated, and the prothrombin activation complexes are stabilized. Modified from Br J Haematol, 131, Esmon CT, The interactions between inflammation and coagulation, 417C430, Copyright (2005),9 with permission from Blackwell Publishing.

Abnormalities in the coagulation system resulting from systemic illnesses, which cause local disturbances in hemostasis, and the thrombotic potential of cancer patients have been described since the time of Virchow. Virchow??s classic triad consists of changes in coagulability, endothelial cell injury, and abnormal blood flow. In septic patients, all three of these classic alterations are present and culminate in reduced blood flow to vital organs. Septic patients frequently have poor tissue perfusion in addition to inappropriate use of oxygen with resulting cytopathic hypoxia.10 The coagulation abnormalities in septic patients are profound and have led to a successful, Food and Drug Administration-approved therapeutic intervention: activated protein C (APC, marketed under the name Xigris; Eli Lilly & Co., Indianapolis, IN).11 The approval of APC was controversial, with half of the Food and Drug Administration panel voting to require a confirmatory trial.12

The successful clinical trials with APC for the treatment of sepsis were initiated following studies in the baboon model of Escherichia coli sepsis.13 There are very few compounds that have successfully made the transition from preclinical sepsis trials to a viable therapeutic option. Approval of APC for the treatment of septic patients clearly demonstrates that alterations in the coagulation system are important in sepsis mortality. Despite the success, the mechanism of action, beyond the coagulation system, has not been fully defined. It has been postulated that APC has anti-inflammatory properties that help to explain the beneficial effects. However, the question of whether excessive inflammation plays a critical role in sepsis mortality has yet to be definitively answered.

Although APC improves survival in patients with severe sepsis, it is clearly not a panacea for all patients. Analysis of the initial data showed that the most beneficial effects were observed in patients with the worst prognosis. Follow-up studies demonstrated that patients at low risk for death had no improvement in survival and had a significantly increased risk of bleeding if treated with activated protein C.14

Aberrant Mediator Production

The inflammatory response represents an important, central component of sepsis because elements of the response drive the physiological alterations that become manifest as the systemic inflammatory response syndrome. An appropriate inflammatory response eliminates the invading microorganisms without causing damage to tissues, organs, or other systems.

Hyperinflammatory Response

Several years ago, many basic science investigators and clinicians believed that the problem of sepsis was directly related to the exuberant production of proinflammatory molecules. The problem seemed rather simple: inflammation was excessive. The solution was easy: blunt inflammation, and save lives. This concept was driven by four pieces of information. First, septic patients with increased levels of specific mediators such as tumor necrosis factor (TNF) are at increased risk for death.15 Second, injection of TNF molecules into experimental animals results in widespread inflammatory alterations16 and tissue injury17 similar to that observed in septic patients. Third, experimental animals injected with lethal doses of endotoxin display elevated levels of the same mediators. Finally, inhibition of these specific mediators improves survival in endotoxin shock models.18 Together, these observations launched a series of clinical trials aimed at blocking TNF or interleukin (IL)-1. The results of these clinical trials are summarized, as recently reviewed19 (Tables 2 and 3) .

Table 2. Clinical Trials with TNF Inhibitors

Although these individual trials did not show significant or dramatic improvements in survival, a meta-analysis of all TNF inhibitors did demonstrate overall improvement.33 Despite these failed endeavors, exploration of new mediators of organ injury should still be explored. Among the potential candidates are high mobility group 1,38 triggering receptor expressed on myeloid cells (TREM),39 and vascular endothelial growth factor.40 Exciting recent work has also emerged on the role of the complement system in sepsis, undoubtedly providing another fruitful area for investigation.41

A frequent explanation put forth for the previous inhibitor trial failures was that the anti-inflammatory agents were not administered quickly enough. The classic endotoxin model of "sepsis" drove much of this thinking. In this model, lethal doses of endotoxin are injected intraperitoneally or intravenously into an experimental animal. Endotoxin induces a massive, rapid release of several proinflammatory molecules, including cytokines in both humans and experimental animals.42 However, subsequent work has shown that models of sepsis that more closely reproduce the clinical situation, such as that caused by cecal ligation and puncture, induce a proinflammatory response that is substantially lower in magnitude and longer in duration than that observed after acute exposure to endotoxin.43,44 In addition, human clinical trials aimed at giving global immunosuppression with high-dose glucocorticoids failed to yield any improvement in survival. Although the cecal ligation and puncture model of sepsis has become widely used, it may not represent the best preclinical model because most septic patients have a pulmonary source of infection (pneumonia) rather than peritoneal. Controversy remains about the best animal model for the study of sepsis.45

In traditional thinking, a mediator must be elevated and detectable to be implicated in the pathogenesis of disease. In septic patients with poor survival, TNF was elevated, and this provided a portion of the rationale on why it should be blocked.15 However, it must be borne in mind that cytokines may have significant effects at the local level such that detectable plasma levels may not be necessary for the cytokine blockade to be effective. This was shown dramatically in a recent clinical trial of neonatal-onset multisystem inflammatory disease where children treated with the IL-1 receptor antagonist demonstrated a remarkable improvement in both objective and subjective criteria.46 This dramatic improvement occurred even though IL-1 was not detectable in the plasma. As one index of improvement, IL-6 levels were significantly decreased with IL-1 receptor antagonist treatment.

Blunted Inflammatory Response

Another viewpoint would argue that septic patients failed to control the bacterial infection and died as a result of immunosuppression rather than immunostimulation. Recent work has shown that intensive care unit patients have reduced production of both TNF and IL-6 in response to endotoxin stimulation.47,48 Another study demonstrated that although TNF was reduced, IL-10 production was not impaired in patients with sepsis.49 These studies would indicate that the proinflammatory response could not be initiated, whereas the anti-inflammatory response continued unabated, producing the equivalent of a blunted inflammatory response. Patients with severe burns and sepsis exhibit defects in their T lymphocytes because the cells fail to proliferate in response to mitogenic stimuli and also fail to produce IL-2 or -12.50,51 Because blocking the inflammatory response with specific inhibitors was not tremendously effective (see Tables 2 and 3 ), the possibility was raised that the patients required immunostimulation. However, in the clinical trial using granulocyte colony-stimulating factor to treat 701 patients with pneumonia and severe sepsis, there was no improvement in survival.52 In a smaller study with 58 patients, granulocyte macrophage colony-stimulating factor also did not improve survival but did decrease length of hospitalization and improve other clinical parameters.53 The blunted monocyte response observed in septic patients has been reversed with interferon-, and systemic therapy successfully cleared sepsis in eight of nine patients.54 A larger clinical trial with 416 trauma patients indicated that interferon- therapy did not reduce infections or overall mortality but did reduce deaths due to infections.55

Unknown Inflammatory Response

The previous data would indicate that the inflammatory response in septic patients is complex and not as neatly defined as enhanced or decreased. Because of this heterogenous response, some patients will benefit from blunting their inflammation, whereas others would be better served by augmenting their inflammatory response. Tailoring the therapy to the individual patient occurs with many diseases, and sepsis should not be an exception. Work with the preclinical model of sepsis has indicated that blunting inflammation only improves survival in those animals at a high risk of dying.56 Clinical evidence favoring a tailored response comes from sepsis trials demonstrating that low-dose glucocorticoid therapy is most effective in those patients with an impaired adrenal response.57

Roger Bone observed, "We should spend more time learning how to achieve an accurate diagnosis and less time searching for a magic bullet."58 In this context, different plasma markers have been proposed as diagnostic markers for the presence of sepsis as well as the severity of sepsis. These molecules may not actually participate in the cell or organ injury but may serve as markers for the presence and severity of sepsis. It must be acknowledged that controversy exists in this area. Some investigators believe that IL-6 serves as a marker of injury,59 whereas others believe that IL-6 may be responsible for the altered pathophysiology.

Defining the precise inflammatory response also represents a significant issue, one frequently debated within my own laboratory. Measuring plasma levels of cytokines is probably not sufficient to determine whether a patient or experimental animal is hyperinflammatory or hypoinflammatory. If only the proinflammatory mediators are measured, then the patient will appear hyperinflammatory. Conversely, if only cytokine antagonists or anti-inflammatory mediators are measured, a person appears to be hypoinflammatory. In fact, both proinflammatory and anti-inflammatory mediators may be circulating at the same time in the plasma.44 Better methods for determining the precise immunological status may be achieved via either a multiplex format for cytokine measurements60 or an evaluation of cellular function.54

Cellular Dysfunction

Many cellular aspects become dysfunctional in sepsis and may be characterized as either excessive activation or depressed function. Excessive activation refers to cells that are primed such that they respond in a very vigorous manner to a second stimulus. An example of excessive activation would be neutrophils generating excess toxic products that cause damage to nearby cells.61 An example of depressed function would be neutrophil failure to phagocytize and clear invading pathogens.

One of the current areas of active investigation concerning cellular function is the induction of cellular apoptosis or necrosis. The signaling mechanisms and molecules that induce apoptosis are currently being described in great detail by a number of investigators. One must carefully evaluate the literature with regards to apoptosis because some detection methodologies suffer from a high rate of false-positive reactions with subsequent controversy concerning the findings.62,63 Apoptosis and necrosis in the field of sepsis have been reviewed quite nicely in the recent past.64,65 Apoptosis may contribute to the pathogenesis of sepsis by delayed removal of those cells that should be removed, ie, neutrophils, and early removal of those cells that should not be removed, ie, lymphocytes.

Lymphocyte Apoptosis

Lymphocytes are critical cells in the response to sepsis, and the interactions between the innate and adaptive immune system are becoming increasingly important. Pioneering studies by Hotchkiss et al have defined that septic patients have significant apoptosis of lymphocytes.62 These apoptotic lymphocytes were observed in virtually all lymphoid organs including the obvious locations, such as the spleen and thymus, but also in the gastric associated lymphatic tissue and essentially wherever collections of lymphocytes exist. These murine experiments were extended in a very interesting study when these investigators performed rapid autopsies in the intensive care unit on patients who died from sepsis.66 It was necessary to perform the autopsies rapidly to collect tissue that did not display substantial postmortem autolysis. Lymphocyte apoptosis may be the cause of the reduced lymphocyte function in septic patients previously described (failure to produce cytokines50,51 ). In septic patients, there is a combination of apoptotic and necrotic cell death. The importance of apoptosis in the pathophysiology of sepsis has been demonstrated in multiple studies.65 It has been shown transfer of apoptotic splenocytes will worsen survival in a mouse model of sepsis, whereas transfer of necrotic splenocytes improves survival.67

Neutrophil Hyperactivity

Neutrophils are critical components of the innate immune response to infectious challenges. Neutropenic patients, regardless of the cause of the neutropenia, and patients with neutrophil dysfunction are at increased risk for the development of infectious complications.68 There is no question that an appropriate, robust neutrophil response benefits the patient and helps to eradicate an infectious focus. The difficulty lies in attempting to define an appropriate response versus a hyperactive response,69 as illustrated in Figure 2 . Patients who have suffered traumatic injury are at increased risk for the development of multisystem organ failure, and neutrophils recovered from such patients demonstrate increased chemotactic responses to CXC chemokines.70 However, neutrophils isolated from septic patients demonstrate decreased chemotaxis toward IL-8 and depressed expression of CXCR2.71 These results were further explored in a article showing that high CXCR2 function correlates with the development of organ injury, ie, acute respiratory distress syndrome, whereas low function predisposes to pneumonia and sepsis.72 These studies aptly demonstrate the heterogeneity of the septic response in that some patients have an excessive response, whereas others have a blunted response.

Figure 2. Proposed model for dysregulation of neutrophil recruitment to bacterial infection in nonpulmonary tissue under normal conditions (left) and in sepsis (right). Colony stimulating factors induce the release of neutrophils from the bone marrow. Under normal conditions, large numbers of the peripheral blood neutrophils enter sites of bacterial infection by first adhering to activated endothelial cells and then migrating along a gradient of chemotactic factors. These chemotactic factors are produced at the local site of infection. Neutrophils use Toll-like receptors (TLR-2 or TLR-4) to interact with pathogen-associated molecular patterns on bacteria to phagocytize and eliminate the pathogens. In contrast, neutrophils from septic patients have increased expression of surface integrins, which promote firm adhesion to endothelial cells. As a consequence, the neutrophils remain bound more tightly to the endothelial cells and fail to migrate appropriately into the site of the bacterial infection. Redrawn from The Lancet, 368, Brown KA, Brain SD, Pearson JD, Edgeworth JD, Lewis SM, Treacher DF, Neutrophils in development of multiple organ failure in sepsis, 157C169, Copyright (2006),69 with permission from Elsevier.

Modulating the recruitment of neutrophils to the site of inflammation has potential benefits, but this should be via specific modulation rather than global inhibition of neutrophil function. Recently, a class of immunomodulatory compounds termed pepducins, which are cell-penetrating lipopeptides, have been used to target CXC chemokine receptors.73 These compounds were able to block neutrophil chemotaxis to CXC chemokines without affecting neutrophil responses to other stimulants such as the formyl peptides. These compounds were used in the murine model of cecal ligation and puncture-induced sepsis, where they were able to significantly improve survival.

Another significant issue concerns inappropriate apoptosis of neutrophils in the septic patients. Neutrophils in the circulation typically have a very short lifespan of approximately 24 hours. However, patients with sepsis have a delay in their neutrophil apoptosis, causing them to persist longer in the bloodstream. This is due to prolonged activation of nuclear factor B and reduced caspase 3 levels.74 As a result, the septic patient has increased numbers of activated cells with the potential to cause organ injury. However, it must be borne in mind that these activated neutrophils are also the precise defenders that are critical in the innate immune response to clear an infection.75

Endothelial Cell Failure and Apoptosis in Other Cells

Endothelial cells reside at the critical interface between the blood and tissue. Intact endothelial cells exhibit anticoagulant properties through elaboration of anticoagulant molecules such as protein C. These cells also serve as a barrier between blood products and procoagulant molecules, such as heparin, residing in the extracellular matrix. Endothelial disruption comes about because of increased expression of adhesion molecules on the endothelial cells, resulting in attachment of white blood cells. It has also become increasingly clear that abundant cross talk exists between the coagulation system and the inflammation system in sepsis.76

Endothelial cells will undergo apoptosis in response to several mediators in vitro, including some infectious agents. However, endothelial cells are relatively resistant to the effects of endotoxin, and several investigators have failed to demonstrate convincing evidence of endothelial cell apoptosis during sepsis.62 Although it is strongly suspected that endothelial cells are dysfunctional in septic patients, clear-cut documentation during in vivo settings has been difficult to obtain. Other cells within the body also fail to function normally, and it has been demonstrated that increased apoptosis of dendritic cells, macrophages/monocytes, and mucosal epithelial cells, among other cells, are present in septic patients.65

Metabolic Alterations

Glycemic Control

Intensive insulin therapy has been shown to improve mortality among critically ill patients in a prospective randomized clinical trial involving 1548 patients.77 The reduced mortality was particularly impressive in those septic patients with a proven focus of infection. There were additional beneficial effects to maintaining strict glucose control including reduced infections, reduced acute renal failure, and decreased muscle wasting and anemia. Consequently, current recommendations for patients in the trauma unit call for strict glycemic control.78 Patients who are critically ill exhibit insulin resistance and hyperglycemia, a condition that has been termed the diabetes of stress. These high blood glucose levels have been shown to decrease the function of polymorphonuclear neutrophils, including diminished bactericidal activity.79 Further analysis of the patients with strict glycemic control indicated that there seems to be substantial protection of the endothelial cells.80 This was manifested by significantly reduced circulating levels of intracellular adhesion molecule-1 on the endothelial cells. However, it should be noted that strict glycemic control is not without controversy.81 There are issues with potential hypoglycemia82 as well as the costs associated with close monitoring.

Low-Dose Steroids

Previous work has demonstrated that high-dose glucocorticoids aimed at blunting the inflammatory response do not provide an improvement in outcome, as recently reviewed.83 In fact, high-dose steroids have been associated with increased mortality in at least one study. Evidence exists that some patients with sepsis have adrenal failure, and these patients benefit from having replacement doses of glucocorticoids administered over a prolonged time.57 The steroids were not used at a dose necessary to blunt the inflammatory response but were given as replacement therapy for a failing organ, in this case, the adrenal gland.

Early Goal-Directed Therapy

An important study by Rivers et al demonstrated that early administration of fluids and blood products to septic patients in the emergency room will significantly improve survival.84 This study was important because the types of fluids and the total volume of fluids did not change; it was only when the fluids were given. The use of more sophisticated monitoring techniques in the emergency room allowed better determination of the resuscitation status of the patient.

Conclusion

Numerous immunopathologic alterations account for the morbidity and mortality of sepsis. Active research by several investigators continues to define the principal alterations in sepsis, though significant challenges remain before this devastating process is understood and conquered. Numerous controversies swirl in the sepsis arena. Critical questions that remained unanswered in 2007 concerning the pathogenesis of sepsis include the following: 1) What is the precise role of coagulopathy in the organ injury and mortality of sepsis? 2) Are septic patients hyperinflammatory or immuno-comprimised? 3) Is there a magic bullet that can be used to improve survival of septic patients? 4) What cellular alterations drive substantial organ injury? 5) How should the metabolic and physiological alterations be appropriately managed? Although advances have been made, much work remains. Understanding the altered pathophysiology will help to guide the management of sepsis.85

Table 3. Clinical Trials Using the Interleukin-1 Receptor Antagonist to Treat Sepsis

Acknowledgements

I thank Dr. Charles Esmon and Benjamin E. Weston for permission to adapt Figures 1 and 2 .

【参考文献】
  Baron RM, Baron MJ, Perrella MA: Pathobiology of sepsis: are we still asking the same questions? Am J Respir Cell Mol Biol 2006, 34:129-134

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

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

: 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 1992, 20:864-874

Robertson CM, Coopersmith CM: The systemic inflammatory response syndrome. Microbes Infect 2006, 8:1382-1389

Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, Cohen J, Opal SM, Vincent JL, Ramsay G, : SCCM/ESICM/ACCP/ATS/SIS: 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med 2003, 31:1250-1256

McMasters KM, Peyton JC, Hadjiminas DJ, Cheadle WG: Endotoxin and tumour necrosis factor do not cause mortality from caecal ligation and puncture. Cytokine 1994, 6:530-536

Esmon CT: Inflammation and the activated protein C anticoagulant pathway. Semin Thromb Hemost 2006, 32(Suppl 1):49-60

Esmon CT: The interactions between inflammation and coagulation. Br J Haematol 2005, 131:417-430

Fink MP: Cytopathic hypoxia. Mitochondrial dysfunction as mechanism contributing to organ dysfunction in sepsis. Crit Care Clin 2001, 17:219-237

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

Eichacker PQ, Natanson C, Danner RL: Surviving sepsis??practice guidelines, marketing campaigns, and Eli Lilly. N Engl J Med 2006, 355:1640-1642

Esmon CT, Taylor FB, Jr, Hinshaw LB, Chang A, Comp PC, Ferrell G, Esmon NL: Protein C, isolation and potential use in prevention of thrombosis. Dev Biol Stand 1987, 67:51-57

Abraham E, Laterre PF, Garg R, Levy H, Talwar D, Trzaskoma BL, Francois B, Guy JS, Bruckmann M, Rea-Neto A, Rossaint R, Perrotin D, Sablotzki A, Arkins N, Utterback BG, Macias WL: Drotrecogin alfa (activated) for adults with severe sepsis and a low risk of death. N Engl J Med 2005, 353:1332-1341

Waage A, Halstensen A, Espevik T: Association between tumour necrosis factor in serum and fatal outcome in patients with meningococcal disease. Lancet 1987, 1:355-357

Remick DG, Kunkel RG, Larrick JW, Kunkel SL: Acute in vivo effects of human recombinant tumor necrosis factor. Lab Invest 1987, 56:583-590

Tracey KJ, Beutler B, Lowry SF, Merryweather J, Wolpe S, Milsark IW, Hariri RJ, Fahey TJ, 3rd, Zentella A, Albert JD, Shires GT, Cerami A: Shock and tissue injury induced by recombinant human cachectin. Science 1986, 234:470-474

Beutler B, Milsark IW, Cerami AC: Passive immunization against cachectin/tumor necrosis factor protects mice from lethal effect of endotoxin. Science 1985, 229:869-871

Remick DG: Cytokine therapeutics for the treatment of sepsis: why has nothing worked? Curr Pharm Des 2003, 9:75-82

Dhainaut JF, Vincent JL, Richard C, Lejeune P, Martin C, Fierobe L, Stephens S, Ney UM, Sopwith M: CDP571, a humanized antibody to human tumor necrosis factor-alpha: safety, pharmacokinetics, immune response, and influence of the antibody on cytokine concentrations in patients with septic shock. CPD571 Sepsis Study Group. Crit Care Med 1995, 23:1461-1469

Fisher CJ, Jr, Opal SM, Dhainaut JF, Stephens S, Zimmerman JL, Nightingale P, Harris SJ, Schein RM, Panacek EA, Vincent JL, Foulke GE, Warren EL, Garrad C, Park G, Bodmer MW, Cohen J, Van der Linden CJ, Cross A, Sadoff JC: Influence of an anti-tumor necrosis factor monoclonal antibody on cytokine levels in patients with sepsis. The CB0006 Sepsis Syndrome Study Group

Rice TW, Wheeler AP, Morris PE, Paz HL, Russell JA, Edens TR, Bernard GR: Safety and efficacy of affinity-purified, anti-tumor necrosis factor-alpha, ovine fab for injection (CytoFab) in severe sepsis. Crit Care Med 2006, 34:2271-2281

Clark MA, Plank LD, Connolly AB, Streat SJ, Hill AA, Gupta R, Monk DN, Shenkin A, Hill GL: Effect of a chimeric antibody to tumor necrosis factor-alpha on cytokine and physiologic responses in patients with severe sepsis??a randomized, clinical trial

Reinhart K, Wiegand-Lohnert C, Grimminger F, Kaul M, Withington S, Treacher D, Eckart J, Willatts S, Bouza C, Krausch D, Stockenhuber F, Eiselstein J, Daum L, Kempeni J: Assessment of the safety and efficacy of the monoclonal anti-tumor necrosis factor antibody-fragment, MAK 195F, in patients with sepsis and septic shock: a multicenter, randomized, placebo-controlled, dose-ranging study

Fisher CJ, Jr, Agosti JM, Opal SM, Lowry SF, Balk RA, Sadoff JC, Abraham E, Schein RM, Benjamin E: Treatment of septic shock with the tumor necrosis factor receptor:Fc fusion protein. The Soluble TNF Receptor Sepsis Study Group. N Engl J Med 1996, 334:1697-1702

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: p55 Tumor necrosis factor receptor fusion protein in the treatment of patients with severe sepsis and septic shock. a randomized controlled multicenter trial. Ro 45-2081 Study Group. JAMA 1997, 277:1531-1538

Cohen J, Carlet J: INTERSEPT: an international, multicenter, placebo-controlled trial of monoclonal antibody to human tumor necrosis factor-alpha in patients with sepsis. International Sepsis Trial Study Group. Crit Care Med 1996, 24:1431-1440

Reinhart K, Menges T, Gardlund B, Harm Zwaveling J, Smithes M, Vincent JL, Tellado JM, Salgado-Remigio A, Zimlichman R, Withington S, Tschaikowsky K, Brase R, Damas P, Kupper H, Kempeni J, Eiselstein J, Kaul M: Randomized, placebo-controlled trial of the anti-tumor necrosis factor antibody fragment afelimomab in hyperinflammatory response during severe sepsis: the RAMSES Study. Crit Care Med 2001, 29:765-769

Abraham E, Wunderink R, Silverman H, Perl TM, Nasraway S, Levy H, Bone R, Wenzel RP, Balk R, Allred R, Pennington JE, Wherry JC: Efficacy and safety of monoclonal antibody to human tumor necrosis factor alpha in patients with sepsis syndrome. A randomized, controlled, double-blind, multicenter clinical trial. TNF-alpha MAb Sepsis Study Group. JAMA 1995, 273:934-941

Abraham E, Laterre PF, Garbino J, Pingleton S, Butler T, Dugernier T, Margolis B, Kudsk K, Zimmerli W, Anderson P, Reynaert M, Lew D, Lesslauer W, Passe S, Cooper P, Burdeska A, Modi M, Leighton A, Salgo M, Van der Auwera P, : Lenercept Study Group: Lenercept (p55 tumor necrosis factor receptor fusion protein) in severe sepsis and early septic shock: a randomized, double-blind, placebo-controlled, multicenter phase III trial with 1,342 patients. Crit Care Med 2001, 29:503-510

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: Double-blind randomised controlled trial of monoclonal antibody to human tumour necrosis factor in treatment of septic shock. NORASEPT II Study Group

Panacek EA, Marshall JC, Albertson 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

Marshall JC: Such stuff as dreams are made on: mediator-directed therapy in sepsis. Nat Rev Drug Discov 2003, 2:391-405

Boermeester MA, van Leeuwen PA, Coyle SM, Wolbink GJ, Hack CE, Lowry SF: Interleukin-1 blockade attenuates mediator release and dysregulation of the hemostatic mechanism during human sepsis. Arch Surg 1995, 130:739-748

Fisher CJ, Jr, Slotman GJ, Opal SM, Pribble JP, Bone RC, Emmanuel G, Ng D, Bloedow DC, Catalano MA: Initial evaluation of human recombinant interleukin-1 receptor antagonist in the treatment of sepsis syndrome: a randomized, open-label, placebo-controlled multicenter trial. The IL-1RA Sepsis Syndrome Study Group. Crit Care Med 1994, 22:12-21

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: Confirmatory interleukin-1 receptor antagonist trial in severe sepsis: a phase III, randomized, double-blind, placebo-controlled, multicenter trial. The Interleukin-1 Receptor Antagonist Sepsis Investigator Group. Crit Care Med 1997, 25:1115-1124

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

Wang H, Bloom O, Zhang M, Vishnubhakat JM, Ombrellino M, Che J, Frazier A, Yang H, Ivanova S, Borovikova L, Manogue KR, Faist E, Abraham E, Andersson J, Andersson U, Molina PE, Abumrad NN, Sama A, Tracey KJ: HMG-1 as a late mediator of endotoxin lethality in mice. Science 1999, 285:248-251

Gibot S, Buonsanti C, Massin F, Romano M, Kolopp-Sarda MN, Benigni F, Faure GC, Bene MC, Panina-Bordignon P, Passini N, Levy B: Modulation of the triggering receptor expressed on the myeloid cell type 1 pathway in murine septic shock. Infect Immun 2006, 74:2823-2830

Yano K, Liaw PC, Mullington JM, Shih SC, Okada H, Bodyak N, Kang PM, Toltl L, Belikoff B, Buras J, Simms BT, Mizgerd JP, Carmeliet P, Karumanchi SA, Aird WC: Vascular endothelial growth factor is an important determinant of sepsis morbidity and mortality. J Exp Med 2006, 203:1447-1458

Niederbichler AD, Hoesel LM, Westfall MV, Gao H, Ipaktchi KR, Sun L, Zetoune FS, Su GL, Arbabi S, Sarma JV, Wang SC, Hemmila MR, Ward PA: An essential role for complement C5a in the pathogenesis of septic cardiac dysfunction. J Exp Med 2006, 203:53-61

Copeland S, Warren HS, Lowry SF, Calvano SE, Remick D: Acute inflammatory response to endotoxin in mice and humans. Clin Diagn Lab Immunol 2005, 12:60-67

Remick DG, Newcomb DE, Bolgos GL, Call DR: Comparison of the mortality and inflammatory response of two models of sepsis: lipopolysaccharide vs. cecal ligation and puncture. Shock 2000, 13:110-116

Osuchowski MF, Welch K, Siddiqui J, Remick DG: Circulating cytokine/inhibitor profiles reshape the understanding of the SIRS/CARS continuum in sepsis and predict mortality. J Immunol 2006, 177:1967-1974

Buras JA, Holzmann B, Sitkovsky M: Animal models of sepsis: setting the stage. Nat Rev Drug Discov 2005, 4:854-865

Goldbach-Mansky R, Dailey NJ, Canna SW, Gelabert A, Jones J, Rubin BI, Kim HJ, Brewer C, Zalewski C, Wiggs E, Hill S, Turner ML, Karp BI, Aksentijevich I, Pucino F, Penzak SR, Haverkamp MH, Stein L, Adams BS, Moore TL, Fuhlbrigge RC, Shaham B, Jarvis JN, O??Neil K, Vehe RK, Beitz LO, Gardner G, Hannan WP, Warren RW, Horn W, Cole JL, Paul SM, Hawkins PN, Pham TH, Snyder C, Wesley RA, Hoffmann SC, Holland SM, Butman JA, Kastner DL: Neonatal-onset multisystem inflammatory disease responsive to interleukin-1beta inhibition. N Engl J Med 2006, 355:581-592

Heagy W, Hansen C, Nieman K, Cohen M, Richardson C, Rodriguez JL, West MA: Impaired ex vivo lipopolysaccharide-stimulated whole blood tumor necrosis factor production may identify "septic" intensive care unit patients. Shock 2000, 14:271-276discussion 276C277

Heagy W, Nieman K, Hansen C, Cohen M, Danielson D, West MA: Lower levels of whole blood LPS-stimulated cytokine release are associated with poorer clinical outcomes in surgical ICU patients. Surg Infect 2003, 4:171-180

Rigato O, Salomao R: Impaired production of interferon-gamma and tumor necrosis factor-alpha but not of interleukin 10 in whole blood of patients with sepsis. Shock 2003, 19:113-116

Rodrick ML, Wood JJ, Grbic JT, O??Mahony JB, Davis CF, Moss NM, Blazar BA, Demling RH, Mannick JA: Defective IL-2 production in patients with severe burns and sepsis. Lymphokine Res 1986, 5:S75-S80

O??Sullivan ST, Lederer JA, Horgan AF, Chin DH, Mannick JA, Rodrick ML: Major injury leads to predominance of the T helper-2 lymphocyte phenotype and diminished interleukin-12 production associated with decreased resistance to infection

Root RK, Lodato RF, Patrick W, Cade JF, Fotheringham N, Milwee S, Vincent JL, Torres A, Rello J, Nelson S, : Pneumonia Sepsis Study G: Multicenter, double-blind, placebo-controlled study of the use of filgrastim in patients hospitalized with pneumonia and severe sepsis. Crit Care Med 2003, 31:367-373

Orozco H, Arch J, Medina-Franco H, Pantoja JP, Gonzalez QH, Vilatoba M, Hinojosa C, Vargas-Vorackova F, Sifuentes-Osornio J: Molgramostim (GM-CSF) associated with antibiotic treatment in nontraumatic abdominal sepsis: a randomized, double-blind, placebo-controlled clinical trial. Arch Surg 2006, 141:150-153discussion 154

Döcke WD, Randow F, Syrbe U, Krausch D, Asadullah K, Reinke P, Volk HD, Kox W: Monocyte deactivation in septic patients: restoration by IFN-gamma treatment. Nat Med 1997, 3:678-681

Dries DJ, Jurkovich GJ, Maier RV, Clemmer TP, Struve SN, Weigelt JA, Stanford GG, Herr DL, Champion HR, Lewis FR: Effect of interferon gamma on infection-related death in patients with severe injuries. A randomized, double-blind, placebo-controlled trial. Arch Surg 1994, 129:1031-1041discussion 1042

Remick DG, Bolgos GE, Siddiqui J: Inflammatory status in sepsis alters efficacy of interleukin-18 binding protein therapy. Crit Care Med 2003, 31:2096-2101

Annane D, Sebille V, Charpentier C, Bollaert PE, Francois B, Korach JM, Capellier G, Cohen Y, Azoulay E, Troche G, Chaumet-Riffaut P, Bellissant E: Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 2002, 288:862-871

Bone RC: Sir Isaac Newton, sepsis, SIRS, and CARS. Crit Care Med 1996, 24:1125-1128

Remick DG, Bolgos GR, Siddiqui J, Shin J, Nemzek JA: Six at six: interleukin-6 measured 6 h after the initiation of sepsis predicts mortality over 3 days. Shock 2002, 17:463-467

Knight PR, Sreekumar A, Siddiqui J, Laxman B, Copeland S, Chinnaiyan A, Remick DG: Development of a sensitive microarray immunoassay and comparison with standard enzyme-linked immunoassay for cytokine analysis. Shock 2004, 21:26-30

Weiss SJ: Tissue destruction by neutrophils

Hotchkiss RS, Dunne WM, Swanson PE, Davis CG, Tinsley KW, Chang KC, Buchman TG, Karl IE: Role of apoptosis in Pseudomonas aeruginosa pneumonia. Science 2001, 294:1783

Grassme H, Jendrossek V, Gulbins E: Molecular mechanisms of bacteria induced apoptosis. Apoptosis 2001, 6:441-445

Oberholzer C, Oberholzer A, Clare-Salzler M, Moldawer LL: Apoptosis in sepsis: a new target for therapeutic exploration. FASEB J 2001, 15:879-892

Wesche DE, Lomas-Neira JL, Perl M, Chung CS, Ayala A: Leukocyte apoptosis and its significance in sepsis and shock. J Leukoc Biol 2005, 78:325-337

Hotchkiss RS, Swanson PE, Freeman BD, Tinsley KW, Cobb JP, Matuschak GM, Buchman TG, Karl IE: Apoptotic cell death in patients with sepsis, shock, and multiple organ dysfunction

Hotchkiss RS, Chang KC, Grayson MH, Tinsley KW, Dunne BS, Davis CG, Osborne DF, Karl IE: Adoptive transfer of apoptotic splenocytes worsens survival, whereas adoptive transfer of necrotic splenocytes improves survival in sepsis. Proc Natl Acad Sci USA 2003, 100:6724-6729

Lekstrom-Himes JA, Gallin JI: Immunodeficiency diseases caused by defects in phagocytes. N Engl J Med 2000, 343:1703-1714

Brown KA, Brain SD, Pearson JD, Edgeworth JD, Lewis SM, Treacher DF: Neutrophils in development of multiple organ failure in sepsis. Lancet 2006, 368:157-169

Bhatia RK, Pallister I, Dent C, Jones SA, Topley N: Enhanced neutrophil migratory activity following major blunt trauma. Injury 2005, 36:956-962

Chishti AD, Shenton BK, Kirby JA, Baudouin SV: Neutrophil chemotaxis and receptor expression in clinical septic shock. Intensive Care Med 2004, 30:605-611

Adams JM, Hauser CJ, Livingston DH, Lavery RF, Fekete Z, Deitch EA: Early trauma polymorphonuclear neutrophil responses to chemokines are associated with development of sepsis, pneumonia, and organ failure. J Trauma 2001, 51:452-456discussion 456C457

Kaneider NC, Agarwal A, Leger AJ, Kuliopulos A: Reversing systemic inflammatory response syndrome with chemokine receptor pepducins. Nat Med 2005, 11:661-665

Taneja R, Parodo J, Jia SH, Kapus A, Rotstein OD, Marshall JC: Delayed neutrophil apoptosis in sepsis is associated with maintenance of mitochondrial transmembrane potential and reduced caspase-9 activity. Crit Care Med 2004, 32:1460-1469

Smith JA: Neutrophils, host defense, and inflammation: a double-edged sword. J Leukoc Biol 1994, 56:672-686

Abraham E: Coagulation abnormalities in acute lung injury and sepsis. Am J Respir Cell Mol Biol 2000, 22:401-404

van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz M, Vlasselaers D, Ferdinande P, Lauwers P, Bouillon R: Intensive insulin therapy in the critically ill patients. N Engl J Med 2001, 345:1359-1367

Cariou A, Vinsonneau C, Dhainaut JF: Adjunctive therapies in sepsis: an evidence-based review. Crit Care Med 2004, 32:S562-S570

Van den Berghe G: How does blood glucose control with insulin save lives in intensive care? J Clin Invest 2004, 114:1187-1195

Langouche L, Vanhorebeek I, Vlasselaers D, Vander Perre S, Wouters PJ, Skogstrand K, Hansen TK, Van den Berghe G: Intensive insulin therapy protects the endothelium of critically ill patients. J Clin Invest 2005, 115:2277-2286

Shapiro NI, Howell MD, Talmor D, Lahey D, Ngo L, Buras J, Wolfe RE, Weiss JW, Lisbon A: Implementation and outcomes of the Multiple Urgent Sepsis Therapies (MUST) protocol. Crit Care Med 2006, 34:1025-1032

Clayton SB, Mazur JE, Condren S, Hermayer KL, Strange C: Evaluation of an intensive insulin protocol for septic patients in a medical intensive care unit. Crit Care Med 2006, 34:2974-2978

Keh D, Sprung CL: Use of corticosteroid therapy in patients with sepsis and septic shock: an evidence-based review. Crit Care Med 2004, 32:S527-S533

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

Russell JA: Management of sepsis. N Engl J Med 2006, 355:1699-1713

作者单位：From the Boston University School of Medicine, Boston, Massachusetts