- Email: [email protected]
Severe Sepsis: New Concepts in Pathogenesis and Management
Severe Sepsis: New Concepts in Pathogenesis and Management WARREN R. SUMMER, MD
S
epsis has been recognized since 1850. Multiorgan dysfunction syndrome (MODS), although alluded to in 1973, is a relatively new concept. Understanding of both severe sepsis and MODS is in a state of clinical evolution.1–3 Sepsis is a heterogeneous process, and accurate delineation of the risk factors for severe sepsis, its course and its outcome have not been fully elucidated. Predisposing conditions are changing with an aging population, new and aggressive anti-inflammatory therapies, and increased invasive procedures or devices.4 Hospital and intensive care unit occurrences of severe sepsis vary from 2% to 11%, with projections of major increases over the next 50 years. The mortality rate ranges from 25% to 80% but may be decreasing depending on the population reported.5 Changing microbiologic origins and resistances will likely produce variable outcome statistics far into the future.6,7 What is agreed upon is that severe sepsis is a major health and economic problem that will only increase in years to come. Fortunately, after a decade of intensive research and many therapeutic failures, we appear to be making improvements in the management of sepsis and its complications with better overall understanding of these conditions and their long-term outcome. The pathogenesis of severe sepsis was unknown through most of the 20th century and was envisioned as a rude unhinging of the machinery of life. In the latter 1900s, uncontrolled inflammation was considered the mechanism for the septic phenotype. However, the frequency of an exaggerated systemic response could be documented in only a minority of patients.8 This was followed by a focus on the imbalance between pro- and anti-inflammatory cascades and the influence of genetic polymorphism.8,9 More than 30 clinical studies based on modulating inflammation were attempted during the past 20 years10,11 but found not to improve outcome in severe sepsis, suggesting a complex pathogenesis unlikely to be altered by a single intervention. Without full underFrom the Section of Pulmonary/Critical Care Medicine, Department of Medicine, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, Louisiana. Correspondence: Warren Summer, MD, 1901 Perdito Street, Suite 3205, New Orleans, LA 70112–1393 (E-mail [email protected]). THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
standing of the mechanisms of severe sepsis or underlying conditions associated with increased risk, we are destined to manage patients inappropriately and to clinically evaluate a variety of “wrong” therapies. This symposium reviews the pathogenesis of sepsis as it currently applies to management strategies that have been introduced in the past few years. Although the first major review of disseminated intravascular coagulation occurred in 1971, it is only recently that basic and clinical studies have suggested that coagulation and endothelial responses are critically involved in multiorgan failure, vascular collapse, and death from severe sepsis.12 However, the interactions between inflammation, clotting, cytotoxic effects of bacteria, and endothelial response still require elucidation. Although disseminated intravascular coagulation and the inflammatory cascade appear linked during sepsis, it is unproven whether microthrombi induce or worsen organ dysfunction.13 In this symposium, Drs. Jagneaux, Taylor, and Kantrow examine the role of coagulation as a fundamental dysfunction during severe sepsis and MODS and focus on the relationships between coagulation, endothelial injury, and inflammation. The authors provide a practical and lucid description of the coagulation cascade and review the association between coagulopathy and progressive organ failure and death in patients with severe sepsis.14 –16 To make good clinical decisions, we would like specific markers during sepsis, similar, for example, to ST segment elevation or Q wave presence in myocardial infarction. Most biologic markers, however, are insensitive, and severity indices are only loosely applicable to individual patient outcome in sepsis. Whether the excitement over improved outcome in a recent randomized control study using activated protein C17 should make this therapy part of the general standard of care of severe sepsis or limited to a particular subset of patients with shock or especially high severity of illness is argued in a pro/con debate by Drs. Rice and Bernard and Drs. Haley et al. Dr. Pinsky provides an extensive review of current evidence of pro- and anti-inflammatory balance in the generation and outcome of severe sepsis and 193
Severe Sepsis
speculates on the interaction between inflammation, coagulation, and endothelial dysfunction. During sepsis, numerous molecules, each capable of augmenting inflammatory or anti-inflammatory responses can be measured in the cell nucleus, on cell surfaces, or in the blood.18 How to evaluate various mediators and potential therapies to alter their interaction with the host are still speculative. Drs. Happel, Nelson, and Summer review evidence that the lung, the most frequently injured organ in severe sepsis,19 plays a major role not only in producing dyspnea, abnormal gas exchange, and entrance for nosocomial infection but also in amplifying the inflammatory process, adding to further extrapulmonary organ injury and altered outcome. These authors succinctly review the development and process of the systemic inflammatory response while emphasizing the concept that the body tries to compartmentalize inflammatory response if possible but often fails when the lung is significantly injured. Drs. Brierre, Kumari, and DeBoisblanc evaluate the recent information related to hormonal therapy with insulin,20 tight glucose control,21 corticosteroid administration,22 and vasopressin.23 The authors provide a concise discussion of sepsis-induced endocrine dysfunction. These therapeutic modalities have potential for interaction with coagulation, inflammatory cascades, and endothelial biology and may improve or adversely interact with recent anticoagulation and anti-inflammatory therapies.24 The process of delivering the appropriate amount of insulin, reaching the targeted glucose level with the least complication and the timing or sequence of vasopressin therapy are reviewed. Whether the improved physiologic parameters with these later therapies can be translated into better patient outcome (lower 30- to 90-day mortality rate) with severe sepsis or septic shock also are examined and recommendations are presented. Recently, several medical societies sponsored a group of experts to develop a series of guidelines for management of severe sepsis/septic shock in an effort to improve awareness and outcomes for this condition.25 The group could find few positive recommendations supported by one or more large randomized clinical trials and identified several therapeutic strategies that have good randomized controlled trial evidence of their ineffectiveness or potential harm. Importantly, the most positive recommendations were of low grade, and one of those multicenter randomized controlled trials has more recently been shown to be based on misunderstanding of basic physiologic principles.26 Thus, although some progress is being made in the overall treatment strategies for sepsis, history suggests that new therapies may not withstand the test of time. Finally, one of the major challenges in managing severe sepsis is delivering care at the end of life. Studies report that patients and their families are 194
dissatisfied with pain control and physician communication in the intensive care unit. Withdrawal of life support and the proportion of deaths preceded by a do-not-resuscitate order vary extensively between institutions.27 Reason suggests we should avoid novel therapies in patients too severely ill to benefit or when not proven to be of value in a specific cohort. However, how to limit therapy is often perceived as a personal matter between the physician and the patient and not a societal issue of limited resources or excessive expense.28 Management of the complicated process of severe sepsis/septic shock remains in its infancy in spite of a long reported scientific awareness. References 1. Bone RC, Balk RA, Cerra FB, et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis: the ACCP/SCCM Consensus Conference Committee. Chest 1992;101:1644 –55. 2. Kraus WA, Sun X, Nystrom O, et al. Evaluation of definitions for sepsis. Chest 1992;101:1656 – 62. 3. Vincent JL, Moreno R, Takala J, et al. The SOFA (SepsisRelated Organ Failure Assessment) score to describe organ dysfunction/failure. Intens Care Med 1996;22:707–10. 4. Angus DC, Wax RS. Epidemiology of sepsis: an update. Crit Care Med 2001;29:S109 –16. 5. Friedman G, Silva E, Vincent JL. Has the mortality of septic shock changed with time. Crit Care Med 1998;26: 2078 – 86. 6. Sands KE, Bates DW, Lanken PN, et al. Epidemiology of sepsis syndrome in 8 academic medical centers: Academic Medical Center Consortium Sepsis Project Working Group. JAMA 1997;278:234 – 40. 7. Opal SM, Cohen J. Clinical Gram-positive sepsis: does it fundamentally differ from Gram-negative bacterial sepsis? Crit Care Med 1999;27:1608 –16. 8. Hotchkiss RS, Karl IE. The pathophysiology and treatment of sepsis. N Engl J Med 2003;348:138 –50. 9. Netea NG, Van der Meer JW, Van Deuren, et al. Proinflammatory cytokines and sepsis syndrome: not enough, or too much of a good thing? Trends Immunol 2003;24:254 – 8. 10. Beutler B. Endotoxin, tumor necrosis factor, and related mediators: new approaches to shock. New Horizons 1993;1: 3–12. 11. Pittet D, Harbarth S, Suter PM, et al. Impact of immunomodulating therapy on morbidity in patients with severe sepsis. Am J Respir Crit Care Med 1999;160:852–7. 12. Vervloet MG, Thijis LG, Hack CE. Derangements of coagulation and fibrinolysis in critically ill patients with sepsis and septic shock. Semin Thromb Hemost 1998;24:33– 44. 13. Hotchkiss RS, Swanson PE, Freeman BD, et al. Apoptotic cell death in patients with sepsis shock, and multiple organ dysfunction. Crit Care Med 1999;27:1230 –51. 14. De Backer D, Creteur J, Preisler JC, et al. Microvascular blood flow is altered in patients with sepsis. Am J Respir Crit Care Med 2002;166:98 –104. 15. Bone RC, Francis PB, Peirce AK. Intravascular coagulation associated with the adult respiratory distress syndrome. Am J Med 1976;61:585–9. 16. Ueno H, Hirasawa H, Oda S, et al. Coagulation/fibrinolysis abnormality and vascular endothelial damage in the pathogenesis of thrombocytopenic multiple organ failure. Crit Care Med 2002;30:2242– 8.
October 2004 Volume 328 Number 4
Summer
17. Bernard GR, Vincent JL, Laterre PF, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001;344:699 –709. 18. Pinsky MR, Vincent JL, Deviere J, et al. Serum cytokine levels in human septic shock: relation to multiple-system organ failure and mortality. Chest 1993;103:565–75. 19. Russell J, Singer J, Bernard G, et al. Changing pattern of organ dysfunction in early human sepsis is related to mortality. Crit Care Med 2000;28:3405–11. 20. Aljada A, Ghanim H, Mohanty P, et al. Insulin inhibits the pro-inflammatory transcription factor early growth response gene-1 (Egr)-1 expression in mononuclear cells (MNC) and reduces plasma tissue factor (TF) and plasminogen activator inhibitor-1 (PAI-1) concentrations. J Clin Endocrinol Metab 2002;87:1419 –22. 21. van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in critically ill patients. N Engl J Med 2001;345:1359 – 67. 22. Annane D, Sebille V, Charpentier C, et al. Effect of treatment with low does of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 2002; 288:862–71.
THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
23. Chen P. Vasopressin: New uses in critical care. Am J Med Sci 2002;324:146 –54. 24. Hamrahian AH, Oseni TS, Arafah BM. Measurements of serum free cortisol in critically ill patients. New Engl J Med 2004;350:1629 –38. 25. Dellinger RP, Carlet JM, Masur H, et al., for the Surviving Sepsis Campaign Management Guidelines Committee. Surviving sepsis campaign guidelines for management of severe sepsis and septic shock. Crit Care Med 2004; 32:858 –73. 26. Clarke EB, Curtis JR, Luce JM, et al., for the Robert Wood Johnson Foundation Critical Care End of-Life Peer Workgroup Members. Quality indicators for end-oflife care in the intensive care unit. Crit Care Med 2003;31: 2255– 62. 27. Berger JT. Ethical challenges of partial do-not-resuscitate (DNR) orders. Placing DNR orders in the context of a life treating condition plan. Arch Intern Med 2003;163:2270 –5. 28. Romberg E, Passler H, Brahms C, et al. Untersuchungen über die allgemeine Pathologie and Therapie der Kreislaufstörung der akuten Infectionskrankheiten. Dtsch Arch Klin Med 1899;64:652.
195
S
epsis has been recognized since 1850. Multiorgan dysfunction syndrome (MODS), although alluded to in 1973, is a relatively new concept. Understanding of both severe sepsis and MODS is in a state of clinical evolution.1–3 Sepsis is a heterogeneous process, and accurate delineation of the risk factors for severe sepsis, its course and its outcome have not been fully elucidated. Predisposing conditions are changing with an aging population, new and aggressive anti-inflammatory therapies, and increased invasive procedures or devices.4 Hospital and intensive care unit occurrences of severe sepsis vary from 2% to 11%, with projections of major increases over the next 50 years. The mortality rate ranges from 25% to 80% but may be decreasing depending on the population reported.5 Changing microbiologic origins and resistances will likely produce variable outcome statistics far into the future.6,7 What is agreed upon is that severe sepsis is a major health and economic problem that will only increase in years to come. Fortunately, after a decade of intensive research and many therapeutic failures, we appear to be making improvements in the management of sepsis and its complications with better overall understanding of these conditions and their long-term outcome. The pathogenesis of severe sepsis was unknown through most of the 20th century and was envisioned as a rude unhinging of the machinery of life. In the latter 1900s, uncontrolled inflammation was considered the mechanism for the septic phenotype. However, the frequency of an exaggerated systemic response could be documented in only a minority of patients.8 This was followed by a focus on the imbalance between pro- and anti-inflammatory cascades and the influence of genetic polymorphism.8,9 More than 30 clinical studies based on modulating inflammation were attempted during the past 20 years10,11 but found not to improve outcome in severe sepsis, suggesting a complex pathogenesis unlikely to be altered by a single intervention. Without full underFrom the Section of Pulmonary/Critical Care Medicine, Department of Medicine, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, Louisiana. Correspondence: Warren Summer, MD, 1901 Perdito Street, Suite 3205, New Orleans, LA 70112–1393 (E-mail [email protected]). THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
standing of the mechanisms of severe sepsis or underlying conditions associated with increased risk, we are destined to manage patients inappropriately and to clinically evaluate a variety of “wrong” therapies. This symposium reviews the pathogenesis of sepsis as it currently applies to management strategies that have been introduced in the past few years. Although the first major review of disseminated intravascular coagulation occurred in 1971, it is only recently that basic and clinical studies have suggested that coagulation and endothelial responses are critically involved in multiorgan failure, vascular collapse, and death from severe sepsis.12 However, the interactions between inflammation, clotting, cytotoxic effects of bacteria, and endothelial response still require elucidation. Although disseminated intravascular coagulation and the inflammatory cascade appear linked during sepsis, it is unproven whether microthrombi induce or worsen organ dysfunction.13 In this symposium, Drs. Jagneaux, Taylor, and Kantrow examine the role of coagulation as a fundamental dysfunction during severe sepsis and MODS and focus on the relationships between coagulation, endothelial injury, and inflammation. The authors provide a practical and lucid description of the coagulation cascade and review the association between coagulopathy and progressive organ failure and death in patients with severe sepsis.14 –16 To make good clinical decisions, we would like specific markers during sepsis, similar, for example, to ST segment elevation or Q wave presence in myocardial infarction. Most biologic markers, however, are insensitive, and severity indices are only loosely applicable to individual patient outcome in sepsis. Whether the excitement over improved outcome in a recent randomized control study using activated protein C17 should make this therapy part of the general standard of care of severe sepsis or limited to a particular subset of patients with shock or especially high severity of illness is argued in a pro/con debate by Drs. Rice and Bernard and Drs. Haley et al. Dr. Pinsky provides an extensive review of current evidence of pro- and anti-inflammatory balance in the generation and outcome of severe sepsis and 193
Severe Sepsis
speculates on the interaction between inflammation, coagulation, and endothelial dysfunction. During sepsis, numerous molecules, each capable of augmenting inflammatory or anti-inflammatory responses can be measured in the cell nucleus, on cell surfaces, or in the blood.18 How to evaluate various mediators and potential therapies to alter their interaction with the host are still speculative. Drs. Happel, Nelson, and Summer review evidence that the lung, the most frequently injured organ in severe sepsis,19 plays a major role not only in producing dyspnea, abnormal gas exchange, and entrance for nosocomial infection but also in amplifying the inflammatory process, adding to further extrapulmonary organ injury and altered outcome. These authors succinctly review the development and process of the systemic inflammatory response while emphasizing the concept that the body tries to compartmentalize inflammatory response if possible but often fails when the lung is significantly injured. Drs. Brierre, Kumari, and DeBoisblanc evaluate the recent information related to hormonal therapy with insulin,20 tight glucose control,21 corticosteroid administration,22 and vasopressin.23 The authors provide a concise discussion of sepsis-induced endocrine dysfunction. These therapeutic modalities have potential for interaction with coagulation, inflammatory cascades, and endothelial biology and may improve or adversely interact with recent anticoagulation and anti-inflammatory therapies.24 The process of delivering the appropriate amount of insulin, reaching the targeted glucose level with the least complication and the timing or sequence of vasopressin therapy are reviewed. Whether the improved physiologic parameters with these later therapies can be translated into better patient outcome (lower 30- to 90-day mortality rate) with severe sepsis or septic shock also are examined and recommendations are presented. Recently, several medical societies sponsored a group of experts to develop a series of guidelines for management of severe sepsis/septic shock in an effort to improve awareness and outcomes for this condition.25 The group could find few positive recommendations supported by one or more large randomized clinical trials and identified several therapeutic strategies that have good randomized controlled trial evidence of their ineffectiveness or potential harm. Importantly, the most positive recommendations were of low grade, and one of those multicenter randomized controlled trials has more recently been shown to be based on misunderstanding of basic physiologic principles.26 Thus, although some progress is being made in the overall treatment strategies for sepsis, history suggests that new therapies may not withstand the test of time. Finally, one of the major challenges in managing severe sepsis is delivering care at the end of life. Studies report that patients and their families are 194
dissatisfied with pain control and physician communication in the intensive care unit. Withdrawal of life support and the proportion of deaths preceded by a do-not-resuscitate order vary extensively between institutions.27 Reason suggests we should avoid novel therapies in patients too severely ill to benefit or when not proven to be of value in a specific cohort. However, how to limit therapy is often perceived as a personal matter between the physician and the patient and not a societal issue of limited resources or excessive expense.28 Management of the complicated process of severe sepsis/septic shock remains in its infancy in spite of a long reported scientific awareness. References 1. Bone RC, Balk RA, Cerra FB, et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis: the ACCP/SCCM Consensus Conference Committee. Chest 1992;101:1644 –55. 2. Kraus WA, Sun X, Nystrom O, et al. Evaluation of definitions for sepsis. Chest 1992;101:1656 – 62. 3. Vincent JL, Moreno R, Takala J, et al. The SOFA (SepsisRelated Organ Failure Assessment) score to describe organ dysfunction/failure. Intens Care Med 1996;22:707–10. 4. Angus DC, Wax RS. Epidemiology of sepsis: an update. Crit Care Med 2001;29:S109 –16. 5. Friedman G, Silva E, Vincent JL. Has the mortality of septic shock changed with time. Crit Care Med 1998;26: 2078 – 86. 6. Sands KE, Bates DW, Lanken PN, et al. Epidemiology of sepsis syndrome in 8 academic medical centers: Academic Medical Center Consortium Sepsis Project Working Group. JAMA 1997;278:234 – 40. 7. Opal SM, Cohen J. Clinical Gram-positive sepsis: does it fundamentally differ from Gram-negative bacterial sepsis? Crit Care Med 1999;27:1608 –16. 8. Hotchkiss RS, Karl IE. The pathophysiology and treatment of sepsis. N Engl J Med 2003;348:138 –50. 9. Netea NG, Van der Meer JW, Van Deuren, et al. Proinflammatory cytokines and sepsis syndrome: not enough, or too much of a good thing? Trends Immunol 2003;24:254 – 8. 10. Beutler B. Endotoxin, tumor necrosis factor, and related mediators: new approaches to shock. New Horizons 1993;1: 3–12. 11. Pittet D, Harbarth S, Suter PM, et al. Impact of immunomodulating therapy on morbidity in patients with severe sepsis. Am J Respir Crit Care Med 1999;160:852–7. 12. Vervloet MG, Thijis LG, Hack CE. Derangements of coagulation and fibrinolysis in critically ill patients with sepsis and septic shock. Semin Thromb Hemost 1998;24:33– 44. 13. Hotchkiss RS, Swanson PE, Freeman BD, et al. Apoptotic cell death in patients with sepsis shock, and multiple organ dysfunction. Crit Care Med 1999;27:1230 –51. 14. De Backer D, Creteur J, Preisler JC, et al. Microvascular blood flow is altered in patients with sepsis. Am J Respir Crit Care Med 2002;166:98 –104. 15. Bone RC, Francis PB, Peirce AK. Intravascular coagulation associated with the adult respiratory distress syndrome. Am J Med 1976;61:585–9. 16. Ueno H, Hirasawa H, Oda S, et al. Coagulation/fibrinolysis abnormality and vascular endothelial damage in the pathogenesis of thrombocytopenic multiple organ failure. Crit Care Med 2002;30:2242– 8.
October 2004 Volume 328 Number 4
Summer
17. Bernard GR, Vincent JL, Laterre PF, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001;344:699 –709. 18. Pinsky MR, Vincent JL, Deviere J, et al. Serum cytokine levels in human septic shock: relation to multiple-system organ failure and mortality. Chest 1993;103:565–75. 19. Russell J, Singer J, Bernard G, et al. Changing pattern of organ dysfunction in early human sepsis is related to mortality. Crit Care Med 2000;28:3405–11. 20. Aljada A, Ghanim H, Mohanty P, et al. Insulin inhibits the pro-inflammatory transcription factor early growth response gene-1 (Egr)-1 expression in mononuclear cells (MNC) and reduces plasma tissue factor (TF) and plasminogen activator inhibitor-1 (PAI-1) concentrations. J Clin Endocrinol Metab 2002;87:1419 –22. 21. van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in critically ill patients. N Engl J Med 2001;345:1359 – 67. 22. Annane D, Sebille V, Charpentier C, et al. Effect of treatment with low does of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 2002; 288:862–71.
THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
23. Chen P. Vasopressin: New uses in critical care. Am J Med Sci 2002;324:146 –54. 24. Hamrahian AH, Oseni TS, Arafah BM. Measurements of serum free cortisol in critically ill patients. New Engl J Med 2004;350:1629 –38. 25. Dellinger RP, Carlet JM, Masur H, et al., for the Surviving Sepsis Campaign Management Guidelines Committee. Surviving sepsis campaign guidelines for management of severe sepsis and septic shock. Crit Care Med 2004; 32:858 –73. 26. Clarke EB, Curtis JR, Luce JM, et al., for the Robert Wood Johnson Foundation Critical Care End of-Life Peer Workgroup Members. Quality indicators for end-oflife care in the intensive care unit. Crit Care Med 2003;31: 2255– 62. 27. Berger JT. Ethical challenges of partial do-not-resuscitate (DNR) orders. Placing DNR orders in the context of a life treating condition plan. Arch Intern Med 2003;163:2270 –5. 28. Romberg E, Passler H, Brahms C, et al. Untersuchungen über die allgemeine Pathologie and Therapie der Kreislaufstörung der akuten Infectionskrankheiten. Dtsch Arch Klin Med 1899;64:652.
195