Pathophysiology of Sepsis
2007; Elsevier BV; Volume: 170; Issue: 5 Linguagem: Inglês
10.2353/ajpath.2007.060872
ISSN1525-2191
Autores Tópico(s)Immune Response and Inflammation
ResumoSepsis 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 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.1Baron RM Baron MJ Perrella MA Pathobiology of sepsis: are we still asking the same questions?.Am J Respir Cell Mol Biol. 2006; 34: 129-134Crossref PubMed Scopus (36) Google Scholar 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.2Angus 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: 1303-1310Crossref PubMed Scopus (6885) Google Scholar 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.3Martin 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: 1546-1554Crossref PubMed Scopus (4977) Google Scholar This study also confirmed the work of Angus et al2Angus 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: 1303-1310Crossref PubMed Scopus (6885) Google Scholar 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.”3Martin 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: 1546-1554Crossref PubMed Scopus (4977) Google Scholar 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.4American 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: 864-874Crossref PubMed Scopus (4949) Google Scholar 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.5Robertson CM Coopersmith CM The systemic inflammatory response syndrome.Microbes Infect. 2006; 8: 1382-1389Crossref PubMed Scopus (118) Google Scholar Severe sepsis is sepsis with dysfunction of a least one organ or organ system, and septic shock is severe sepsis with hypotension.Table 1Criteria for the Systemic Inflammatory Response Syndrome, Adapted from the American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference4American 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: 864-874Crossref PubMed Scopus (4949) Google ScholarTwo or more of the following are required:1) Body temperature >38°C or 90 beats per minute3) Respiratory rate >20 breaths per minute or arterial CO2 tension less than 32 mm Hg or a need for mechanical ventilation4) White blood count greater than 12,000/mm3 or 10% immature formsSepsis represents SIRS, which has been induced by an infection. Open table in a new tab Sepsis represents SIRS, which has been induced by an infection. The 2001 International Sepsis Definitions Conference modified the model of SIRS and developed an expanded view of sepsis after revisiting the literature.6Levy 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: 1250-1256Crossref PubMed Scopus (4847) Google Scholar 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.3Martin 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: 1546-1554Crossref PubMed Scopus (4977) Google Scholar 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.7McMasters KM Peyton JC Hadjiminas DJ Cheadle WG Endotoxin and tumour necrosis factor do not cause mortality from caecal ligation and puncture.Cytokine. 1994; 6: 530-536Crossref PubMed Scopus (34) Google Scholar 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. 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.8Esmon CT Inflammation and the activated protein C anticoagulant pathway.Semin Thromb Hemost. 2006; 32: 49-60Crossref PubMed Scopus (228) Google Scholar During inflammatory situations such as sepsis, significant alterations occur at multiple levels within both the coagulation system and the cells that regulate this system9Esmon CT The interactions between inflammation and coagulation.Br J Haematol. 2005; 131: 417-430Crossref PubMed Scopus (757) Google Scholar (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. 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.10Fink MP Cytopathic hypoxia. Mitochondrial dysfunction as mechanism contributing to organ dysfunction in sepsis.Crit Care Clin. 2001; 17: 219-237Abstract Full Text Full Text PDF PubMed Scopus (265) Google Scholar 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).11Bernard GR Vincent JL Laterre PF LaRosa SP Dhainaut JF Lopez-Rodriguez A Steingrub JS Garber GE Helterbrand JD Ely EW Fisher Jr, CJ 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: 699-709Crossref PubMed Scopus (5147) Google Scholar The approval of APC was controversial, with half of the Food and Drug Administration panel voting to require a confirmatory trial.12Eichacker PQ Natanson C Danner RL Surviving sepsis—practice guidelines, marketing campaigns, and Eli Lilly.N Engl J Med. 2006; 355: 1640-1642Crossref PubMed Scopus (164) Google Scholar The successful clinical trials with APC for the treatment of sepsis were initiated following studies in the baboon model of Escherichia coli sepsis.13Esmon CT Taylor Jr, FB 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: 51-57PubMed Google Scholar 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.14Abraham 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: 1332-1341Crossref PubMed Scopus (783) Google Scholar 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. 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.15Waage A Halstensen A Espevik T Association between tumour necrosis factor in serum and fatal outcome in patients with meningococcal disease.Lancet. 1987; 1: 355-357Abstract PubMed Scopus (931) Google Scholar Second, injection of TNF molecules into experimental animals results in widespread inflammatory alterations16Remick DG Kunkel RG Larrick JW Kunkel SL Acute in vivo effects of human recombinant tumor necrosis factor.Lab Invest. 1987; 56: 583-590PubMed Google Scholar and tissue injury17Tracey KJ Beutler B Lowry SF Merryweather J Wolpe S Milsark IW Hariri RJ Fahey 3rd, TJ Zentella A Albert JD Shires GT Cerami A Shock and tissue injury induced by recombinant human cachectin.Science. 1986; 234: 470-474Crossref PubMed Scopus (2239) Google Scholar 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.18Beutler B Milsark IW Cerami AC Passive immunization against cachectin/tumor necrosis factor protects mice from lethal effect of endotoxin.Science. 1985; 229: 869-871Crossref PubMed Scopus (1981) Google Scholar 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 reviewed19Remick DG Cytokine therapeutics for the treatment of sepsis: why has nothing worked?.Curr Pharm Des. 2003; 9: 75-82Crossref PubMed Scopus (111) Google Scholar (Table 2, Table 3).Table 2Clinical Trials with TNF InhibitorsYearNo. of PatientsInhibitorOutcome199542Humanized antibodySafety study. 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A randomized, controlled, double-blind, multicenter clinical trial. 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NORASEPT II Study Group [See comments].Lancet. 1998; 351: 929-933Abstract Full Text Full Text PDF PubMed Scopus (608) Google Scholar20042634F(ab′)2 monoclonal antibodyPatients stratified by IL-6 levels, TNF inhibition resulted in improved survival32Panacek 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: 2173-2182Crossref PubMed Scopus (303) Google ScholarThe table is arranged by increasing numbers of patients enrolled in the trial. A meta-analysis of all of the trials together indicates that there is a survival advantage when using the TNF inhibitors.33Marshall JC Such stuff as dreams are made on: mediator-directed therapy in sepsis.Nat Rev Drug Discov. 2003; 2: 391-405Crossref PubMed Scopus (221) Google Scholar Open table in a new tab Table 3Clinical Trials Using the Interleukin-1 Receptor Antagonist to Treat SepsisYearNo. of PatientsOutcome199526Reduction in surrogate activation markers34Boermeester 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: 739-748Crossref PubMed Scopus (102) Google Scholar199499Dose-related reduction in APACHE score35Fisher Jr, CJ 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: 12-21Crossref PubMed Google Scholar1997696No improvement in survival36Opal SM Fisher Jr, CJ 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: 1115-1124Crossref PubMed Scopus (717) Google Scholar1994893No reduction in 28-day mortality37Fisher Jr, CJ 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: 1836-1843Crossref PubMed Scopus (979) Google ScholarNone of the trials demonstrated an improvement in survival. Open table in a new tab The table is arranged by increasing numbers of patients enrolled in the trial. A meta-analysis of all of the trials together indicates that there is a survival advantage when using the TNF inhibitors.33Marshall JC Such stuff as dreams are made on: mediator-directed therapy in sepsis.Nat Rev Drug Discov. 2003; 2: 391-405Crossref PubMed Scopus (221) Google Scholar None of the trials demonstrated an improvement in survival. Although these individual trials did not show significant or dramatic improvements in survival, a meta-analysis of all TNF inhibitors did demonstrate overall improvement.33Marshall JC Such stuff as dreams are made on: mediator-directed therapy in sepsis.Nat Rev Drug Discov. 2003; 2: 391-405Crossref PubMed Scopus (221) Google Scholar Despite these failed endeavors, exploration of new mediators of organ injury should still be explored. Among the potential candidates are high mobility group 1,38Wang 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: 248-251Crossref PubMed Scopus (3023) Google Scholar triggering receptor expressed on myeloid cells (TREM),39Gibot 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: 2823-2830Crossref PubMed Scopus (97) Google Scholar and vascular endothelial growth factor.40Yano 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: 1447-1458Crossref PubMed Scopus (239) Google Scholar Exciting recent work has also emerged on the role of the complement system in sepsis, undoubtedly providing another fruitful area for investigation.41Niederbichler 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: 53-61Crossref PubMed Scopus (125) Google Scholar 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.42Copeland S Warren HS Lowry SF Calvano SE Remick D Acute inflammatory response to endotoxin in mice and humans.Clin Diagn Lab Immunol. 2005; 12: 60-67Crossref PubMed Scopus (338) Google Scholar 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.43Remick 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: 110-116Crossref PubMed Scopus (441) Google Scholar, 44Osuchowski 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: 1967-1974PubMed Google Scholar In addition, human clinical trials aimed at giving glo
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