’
Definitions and Pathophysiology of Sepsis Mayer Sagy, MD, Yasir Al-Qaqaa, MD, and Paul Kim, MD
Mortality rates for sepsis and septic shock have not improved in the past decade. The Surviving Sepsis Campaign (SSC) guidelines released in 2012 emphasize early recognition and treatment of sepsis, in an effort to reduce the burden of sepsis worldwide. This series of review articles will discuss the pathophysiology of
sepsis; comorbidities, such as multiorgan dysfunction syndrome (MODS), acute respiratory distress syndrome (ARDS), and endocrine issues; and finally, management of sepsis and septic shock.
he word “sepsis” comes from the Greek word “sepo” meaning decay or decomposition. While many years ago the term sepsis meant severe bacterial infection that resulted in decomposition of body tissues, it has, more recently (in 1989), been defined as a syndrome.1,2 Thus, the definition of “Sepsis Syndrome” encompasses multiple signs and symptoms that emanate from the body's response to invading microorganisms. It is now clear that the sepsis syndrome may result from bacterial, fungal, viral, and parasitic infections that trigger the release of inflammatory mediators and induce cellular dysfunction in the affected host.3,4 Patients suffering from this syndrome may have hypothermia or hyperthermia, tachycardia, tachypnea, and at least one end-organ dysfunction due to inadequate perfusion. Patients therefore may present with organ-specific dysfunction such as altered cerebral function (brain), hypoxemia (lungs), elevated plasma lactate (soft tissues), and oliguria (kidneys). The American College of Chest Physicians (ACCP) and the Society of Critical Care Medicine (SCCM) convened a Consensus Conference in 1991 in an attempt to redefine various critical illnesses. One of the end results of that conference was a new term, “Systemic Inflammatory Response Syndrome” (SIRS). The diagnosis of SIRS required that at least two of the following four clinical criteria are met: hyperthermia or hypothermia; tachypnea; tachycardia; and leucocytosis
or leukopenia with immature neutrophils.5,6 However, SIRS was recognized as a nonspecific response to various conditions apart from infections, such as pancreatitis, trauma, ischemia/reperfusion injury, and burns. In a sepsis definition conference held in 2001, 29 international experts in the field of sepsis were gathered to redefine sepsis, severe sepsis, and septic shock. They concluded that the previous definition of 1991 was still useful for clinical practice and research purposes. However, specific categories of sepsis were defined; it was suggested that “Sepsis” would be defined as the presence of infection along with other listed general systemic signs and symptoms. “Severe Sepsis” would be defined as sepsis complicated by at least one organ dysfunction and “Septic Shock” would be defined as severe sepsis with acute circulatory failure that may be characterized by persistent arterial hypotension unexplained by other causes.6 Participants at the Sepsis Definitions Conference suggested that patients with sepsis should also be stratified by laboratory and clinical criteria according to four key aspects: predisposing factors, the infection, the host response, and organ dysfunction. To that end, the PIRO system (Table 1) was created.7,8 In summary, the definition criteria for SIRS or sepsis included identical symptoms (Table 2).
T
From the NYU Langone Medical Center, Division of Pediatric Critical Care Medicine, New York, NY. Curr Probl Pediatr Adolesc Health Care 2013;43:260-263 1538-5442/$ - see front matter & 2013 Mosby, Inc. All rights reserved. http://dx.doi.org/10.1016/j.cppeds.2013.10.001
260
Curr Probl Pediatr Adolesc Health Care 2013;43:260-263
Pathophysiology Possible Mechanisms The pathogenesis of the sepsis syndrome or SIRS can be explained by three mechanisms, all of which
Curr Probl Pediatr Adolesc Health Care, November/December 2013
TABLE 1. The PIRO grading system7
Variables
Laboratory results
Clinical findings
Predisposing factors Infection Response Organ dysfunction
Genetic abnormality Identification of causative microorganisms WBC, coagulation profile, CRP, and lactate levels PaO2/FiO2 ratio, bilirubin, creatinine, and CSF chemistry
Age and comorbidities Site of infection Core temperature, heart rate, blood pressure, and cardiac function Glasgow Coma Scale, urine output, and capillary refill
involve the release of mediators Phases of Inflammatory that result in systemic inflammatory The pathogenesis of the Response11,12 6,9,10 response. Sepsis Syndrome or SIRS There are 3 phases in the pathoMechanism 1: The Pro-inflamcan be explained by three genesis of SIRS: (1) release of matory Response bacterial toxins, (2) release of medimechanisms, all of which The theory behind this mechaators, and (3) effects of excessive nism relates to excessive release involve the release of mediof pro-inflammatory mediators that ators that result in systemic specific mediators. cause inflammation and result in the inflammatory response. Phase 1: Release of Bacterial clinical picture of SIRS. Toxins Mechanism 2: Failure of the Bacterial invasion into the body Compensatory Anti-inflammatory tissues is a source of dangerous toxins. These toxins Response (CARS) to Act may or may not be neutralized and cleared by the An imbalance between pro-inflammatory response existing immune system. The following toxins are and anti-inflammatory response is believed to occur commonly released by Gram-negative and Gramduring infection. This permits the pro-inflammatory positive bacteria: mediators to induce an uncontrolled excessive inflammatory process. Gram-negative bacteria: Mechanism 3: Immunoparalysis ○ Lipopolysaccharide (LPS) Mediators of inflammation overwhelm the existing Gram-positive bacteria: immune system and paralyze it. This induces an ○ Microbial-associated molecular pattern (MAMP) acquired state of immune deficiency, leading to an ○ Lipoteichoic acid (LPA) inability to neutralize pathogens. ○ Muramyl dipeptides (MDP) ○ Superantigens ○ Staphylococcal Toxic Shock Syndrome Toxin (TSST) TABLE 2. Criteria and signs/symptoms to define sepsis ○ Streptococcal Pyrogenic Exotoxin (SPE) SIRS or sepsis criteria
Specific signs/symptoms
Hyperthermia/ Hemodynamic Arterial hypotension hypothermia Tachycardia Increased cardiac output with vasodila Tachypnea tion (low systemic vascular resistance) Changes in white blood Changes in skin perfusion Decreased urine output cell count Positive fluid balance Hyperlactatemia (increased base deficit) with edema Organ dysfunction Hypoxia Altered mental status Hyperglycemia Coagulopathy/DIC Impaired liver function Intolerance to GI feeds (paralytic ileus) 2001 SCCM/ESICM/ACCP/ATS/SIS. International Sepsis Definitions Conference. Crit Care Med. 2003; 31:1250–1256.
Curr Probl PediatrAdolesc Health Care, November/December 2013
Phase 2: Release of Mediators in Response to Infections13–15 1. Gram-negative and Gram-positive bacterial infections with endotoxin release The effects of the release of endotoxins, such as lipopolysacharides (LPS), are commonly expected to occur during Gram-negative infections. Similarly, in Gram-positive infections, lipoteichoic acid (LTA) is expected to be released. Both toxins affect macrophage function and result in production of mediators. This process
261
Fig 1. The effect of endotoxin on macrophage release of mediators of inflammation.
involves toll-like receptors (TLR)-2 and TLR-4; these receptors, along with the co-receptor CD14, recognize the aforementioned toxins as they adhere to the macrophages' walls. While LPS requires a LPS-binding protein (LBP) before it is recognized by the macrophage's TLR-4, LTA, on the other hand, adheres directly and independently to the macrophage's TLR-2 (Fig 1). 2. Gram-positive bacterial infections with exotoxin (superantigen) release The superantigens activate T-lymphocytes and trigger production of interleukin 2 (IL-2) and interferon gamma (IFN-γ). IL-2 is a pro-inflammatory mediator necessary for the growth, proliferation, and differentiation of T cells to become “effector” T cells with enhanced immunologic memory. IFN-γ is a mediator with anti-viral, immunoregulatory, and anti-tumor properties. It also activates inducible nitric oxide synthase and promotes leukocyte migration. Both, IL-2 and IFN-γ trigger macrophages to release IL-1 and tumor necrosis factor alpha. These mediators are important stimulants for generating
an inflammatory response by the body in response to infections (Fig 2). 3. Mediators (cytokines) role in sepsis11,16–19 There are two types of mediators that are released in response to infection, pro- and anti-inflammatory mediators (Table 3). It is assumed that the inflammatory response that characterizes sepsis results from excessive pro-inflammatory mediators while the compensatory anti-inflammatory reaction (CARS) fails to cause adequate immunosuppression. Similarly, if CARS is triggered in an excessive manner, immunoparalysis occurs, enabling existing infections to flare up. Pro-Inflammatory Cytokines. Macrophage stimulation causes production of large amounts of tumor necrosis factor alpha (TNF-α), interleukin 1 (IL-1), and IL-6. TNF-α is one of the most important cytokines involved in the pathophysiology of sepsis and is released early in the process. Other pro-inflammatory mediators facilitate inflammation by promoting endothelial cell–leukocyte adhesion, inducing the release of nitric oxide, arachidonic acid metabolites, and activating the complement cascade. In addition, pro-inflammatory mediators promote coagulation by increasing tissue-coagulation factor levels and membrane coagulants. They also inhibit anticoagulant activity by decreasing thrombomodulin and by inhibiting fibrinolysis. Anti-Inflammatory Cytokines. In contrast to pro-inflammatory cytokines, anti-inflammatory mediators inhibit inflammation by inhibiting TNF-α, augmenting acutephase reactants and immunoglobulins, and inhibiting T-lymphocyte functions. Anti-inflammatory mediators also inhibit activation of the coagulation system. The anti-inflammatory response serves as a negative feedback mechanism to down-regulate the synthesis of proinflammatory mediators and modulate their effects, thereby restoring homeostasis and preventing SIRS.
Phase 3: The Effects of Excessive Specific Mediators
Fig 2. Effect of exotoxin (superantigen) on release of mediators of inflammation.
i. Pro-inflammatory mediators facilitate inflammation by promoting endothelial cell–leukocyte adhesion, inducing the release of arachidonic acid metabolites and complement activation. In addition, pro-inflammatory mediators induce vasodilation by excessive production of NO,
262
Curr Probl Pediatr Adolesc Health Care, November/December 2013
TABLE 3. Mediators in sepsis
Pro-inflammatory mediators
Anti-inflammatory mediators
TNF-α IL1b, IL-2, IL-8, IL-15 Neutrophil elastase IFN-γ Thromboxane, platelet-activating factor Vasoactive neuropeptides Plasminogen activator inhibitor-1 Prostaglandins, prostacyclin Free radical generation Soluble adhesion molecules Tyrosine kinase, Protein kinase H2S, NO HMGB1 protein
IL-1Ra IL-4 IL-10 IL-13 Type II IL-1 receptor Transforming growth factor-β Epinephrine phospholipase A2 Epinephrine phospholipase A2 Soluble TNF-α receptor Leukotriene B4-receptor antagonist LPS-binding protein Soluble recombinant CD-14
Adapted with permission from Bone et al.6
they increase coagulation by an increased release of tissue factors and membrane coagulants, inhibit anticoagulant activity by decreasing thrombomodulin and inhibiting fibrinolysis. ii. In contrast, anti-inflammatory mediators inhibit inflammation by inhibiting TNF-α, augmenting acute-phase reactants and immunoglobulins, and inhibiting T-lymphocyte and macrophage functions. Anti-inflammatory mediators also inhibit activation of the coagulation system by cytokines. The anti-inflammatory response serves as a negative feedback mechanism to downregulate the synthesis of pro-inflammatory mediators, modulate their effects, and thereby restore homeostasis. iii. SIRS results from an excessive pro-inflammatory response. By contrast, an excessive compensatory anti-inflammatory reaction (CARS) results in an inappropriate immunosuppression. If an imbalance develops between SIRS and CARS, homeostasis is violated and a clinical progression towards multiorgan dysfunction may occur.
References 1. Geroulanos S, Douka ET. Historical perspective of the word ‘‘sepsis”. Intensive Care Med 2006;32:2077. 2. Vincent JL, Abraham E. The last 100 years of sepsis. Am J Respir Crit Care Med 2006;173:256–63. 3. Bone RC, Fisher CJ, Clemmer TP, et al. Sepsis syndrome: a valid clinical entity. Crit Care Med 1989;17:389–93. 4. Bone RC. Why new definitions of sepsis are needed. Am J Med 1993;95:348–50.
Curr Probl PediatrAdolesc Health Care, November/December 2013
5. Poeze M, Ramsay G, Gerlach H, et al. An international sepsis survey: a study of doctors' knowledge and perception about sepsis. Crit Care 2004;8:R409–13. 6. Bone RC, Grodzin CJ, Balk RA. Sepsis: a new hypothesis for pathogenesis of the disease process. Chest 1997;112:235–43. 7. ACCP-SCCM Consensus Conference. Definitions of sepsis and multiple organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med 1992;20:864–74. 8. Angus DC, Burgner D, Wunderink R, et al. The PIRO concept: P is for predisposition. Crit Care 2003;7(3):248–451. 9. Bone RC. The pathogenesis of sepsis. Ann Intern Med 1991;115:457–69. 10. Glauser MP, Zanetti G, Baumberger JD, Cohen J. Septic shock: pathogenesis. Lancet 1991;338:732–6. 11. Bhatia M, Moochhala S. Role of inflammatory mediators in the pathophysiology of acute respiratory distress syndrome. J Pathol 2004;202:145–56. 12. Gogos CA, Drosou E, Bassaris HP, Skoutelis A. Pro-versus anti-inflammatory cytokine profile in patients with severe sepsis: a marker for prognosis and future therapeutic options. J Infect Dis 2000;181:176–80. 13. Underhill DM, Ozinsky A. Toll-like receptors: key mediators of microbe detection. Curr Opin Immunol 2002;14:103–10. 14. Underhill DM. Toll-like receptors: networking for success. Eur J Immunol 2003;33:1767–75. 15. Vasselon T, Detmers PA. Toll receptors: a central element in innate immune responses. Infect Immun 2002;70:1033–41. 16. Evans TJ. The role of macrophages in septic shock. Immunobiology 1996;195:655–9. 17. Mathison JC, Wolfson E, Ulevitch RJ. Participation of tumor necrosis factor in the mediation of Gram negative bacterial lipopolysaccharide-induced injury in rabbits. J Clin Invest 1988;81:1925–37. 18. Tracey KJ, Cerami A. Tumor necrosis factor: a pleiotropic cytokine and therapeutic target. Annu Rev Med 1994;45: 491–503. 19. Opal SM, Cohen J. Clinical Gram-positive sepsis: does it fundamentally differ from Gram-negative bacterial sepsis? Crit Care Med 1999;27:1608–16.
263
Definitions and Pathophysiology of Sepsis Mayer Sagy, MD, Yasir Al-Qaqaa, MD, and Paul Kim, MD
Mortality rates for sepsis and septic shock have not improved in the past decade. The Surviving Sepsis Campaign (SSC) guidelines released in 2012 emphasize early recognition and treatment of sepsis, in an effort to reduce the burden of sepsis worldwide. This series of review articles will discuss the pathophysiology of
sepsis; comorbidities, such as multiorgan dysfunction syndrome (MODS), acute respiratory distress syndrome (ARDS), and endocrine issues; and finally, management of sepsis and septic shock.
he word “sepsis” comes from the Greek word “sepo” meaning decay or decomposition. While many years ago the term sepsis meant severe bacterial infection that resulted in decomposition of body tissues, it has, more recently (in 1989), been defined as a syndrome.1,2 Thus, the definition of “Sepsis Syndrome” encompasses multiple signs and symptoms that emanate from the body's response to invading microorganisms. It is now clear that the sepsis syndrome may result from bacterial, fungal, viral, and parasitic infections that trigger the release of inflammatory mediators and induce cellular dysfunction in the affected host.3,4 Patients suffering from this syndrome may have hypothermia or hyperthermia, tachycardia, tachypnea, and at least one end-organ dysfunction due to inadequate perfusion. Patients therefore may present with organ-specific dysfunction such as altered cerebral function (brain), hypoxemia (lungs), elevated plasma lactate (soft tissues), and oliguria (kidneys). The American College of Chest Physicians (ACCP) and the Society of Critical Care Medicine (SCCM) convened a Consensus Conference in 1991 in an attempt to redefine various critical illnesses. One of the end results of that conference was a new term, “Systemic Inflammatory Response Syndrome” (SIRS). The diagnosis of SIRS required that at least two of the following four clinical criteria are met: hyperthermia or hypothermia; tachypnea; tachycardia; and leucocytosis
or leukopenia with immature neutrophils.5,6 However, SIRS was recognized as a nonspecific response to various conditions apart from infections, such as pancreatitis, trauma, ischemia/reperfusion injury, and burns. In a sepsis definition conference held in 2001, 29 international experts in the field of sepsis were gathered to redefine sepsis, severe sepsis, and septic shock. They concluded that the previous definition of 1991 was still useful for clinical practice and research purposes. However, specific categories of sepsis were defined; it was suggested that “Sepsis” would be defined as the presence of infection along with other listed general systemic signs and symptoms. “Severe Sepsis” would be defined as sepsis complicated by at least one organ dysfunction and “Septic Shock” would be defined as severe sepsis with acute circulatory failure that may be characterized by persistent arterial hypotension unexplained by other causes.6 Participants at the Sepsis Definitions Conference suggested that patients with sepsis should also be stratified by laboratory and clinical criteria according to four key aspects: predisposing factors, the infection, the host response, and organ dysfunction. To that end, the PIRO system (Table 1) was created.7,8 In summary, the definition criteria for SIRS or sepsis included identical symptoms (Table 2).
T
From the NYU Langone Medical Center, Division of Pediatric Critical Care Medicine, New York, NY. Curr Probl Pediatr Adolesc Health Care 2013;43:260-263 1538-5442/$ - see front matter & 2013 Mosby, Inc. All rights reserved. http://dx.doi.org/10.1016/j.cppeds.2013.10.001
260
Curr Probl Pediatr Adolesc Health Care 2013;43:260-263
Pathophysiology Possible Mechanisms The pathogenesis of the sepsis syndrome or SIRS can be explained by three mechanisms, all of which
Curr Probl Pediatr Adolesc Health Care, November/December 2013
TABLE 1. The PIRO grading system7
Variables
Laboratory results
Clinical findings
Predisposing factors Infection Response Organ dysfunction
Genetic abnormality Identification of causative microorganisms WBC, coagulation profile, CRP, and lactate levels PaO2/FiO2 ratio, bilirubin, creatinine, and CSF chemistry
Age and comorbidities Site of infection Core temperature, heart rate, blood pressure, and cardiac function Glasgow Coma Scale, urine output, and capillary refill
involve the release of mediators Phases of Inflammatory that result in systemic inflammatory The pathogenesis of the Response11,12 6,9,10 response. Sepsis Syndrome or SIRS There are 3 phases in the pathoMechanism 1: The Pro-inflamcan be explained by three genesis of SIRS: (1) release of matory Response bacterial toxins, (2) release of medimechanisms, all of which The theory behind this mechaators, and (3) effects of excessive nism relates to excessive release involve the release of mediof pro-inflammatory mediators that ators that result in systemic specific mediators. cause inflammation and result in the inflammatory response. Phase 1: Release of Bacterial clinical picture of SIRS. Toxins Mechanism 2: Failure of the Bacterial invasion into the body Compensatory Anti-inflammatory tissues is a source of dangerous toxins. These toxins Response (CARS) to Act may or may not be neutralized and cleared by the An imbalance between pro-inflammatory response existing immune system. The following toxins are and anti-inflammatory response is believed to occur commonly released by Gram-negative and Gramduring infection. This permits the pro-inflammatory positive bacteria: mediators to induce an uncontrolled excessive inflammatory process. Gram-negative bacteria: Mechanism 3: Immunoparalysis ○ Lipopolysaccharide (LPS) Mediators of inflammation overwhelm the existing Gram-positive bacteria: immune system and paralyze it. This induces an ○ Microbial-associated molecular pattern (MAMP) acquired state of immune deficiency, leading to an ○ Lipoteichoic acid (LPA) inability to neutralize pathogens. ○ Muramyl dipeptides (MDP) ○ Superantigens ○ Staphylococcal Toxic Shock Syndrome Toxin (TSST) TABLE 2. Criteria and signs/symptoms to define sepsis ○ Streptococcal Pyrogenic Exotoxin (SPE) SIRS or sepsis criteria
Specific signs/symptoms
Hyperthermia/ Hemodynamic Arterial hypotension hypothermia Tachycardia Increased cardiac output with vasodila Tachypnea tion (low systemic vascular resistance) Changes in white blood Changes in skin perfusion Decreased urine output cell count Positive fluid balance Hyperlactatemia (increased base deficit) with edema Organ dysfunction Hypoxia Altered mental status Hyperglycemia Coagulopathy/DIC Impaired liver function Intolerance to GI feeds (paralytic ileus) 2001 SCCM/ESICM/ACCP/ATS/SIS. International Sepsis Definitions Conference. Crit Care Med. 2003; 31:1250–1256.
Curr Probl PediatrAdolesc Health Care, November/December 2013
Phase 2: Release of Mediators in Response to Infections13–15 1. Gram-negative and Gram-positive bacterial infections with endotoxin release The effects of the release of endotoxins, such as lipopolysacharides (LPS), are commonly expected to occur during Gram-negative infections. Similarly, in Gram-positive infections, lipoteichoic acid (LTA) is expected to be released. Both toxins affect macrophage function and result in production of mediators. This process
261
Fig 1. The effect of endotoxin on macrophage release of mediators of inflammation.
involves toll-like receptors (TLR)-2 and TLR-4; these receptors, along with the co-receptor CD14, recognize the aforementioned toxins as they adhere to the macrophages' walls. While LPS requires a LPS-binding protein (LBP) before it is recognized by the macrophage's TLR-4, LTA, on the other hand, adheres directly and independently to the macrophage's TLR-2 (Fig 1). 2. Gram-positive bacterial infections with exotoxin (superantigen) release The superantigens activate T-lymphocytes and trigger production of interleukin 2 (IL-2) and interferon gamma (IFN-γ). IL-2 is a pro-inflammatory mediator necessary for the growth, proliferation, and differentiation of T cells to become “effector” T cells with enhanced immunologic memory. IFN-γ is a mediator with anti-viral, immunoregulatory, and anti-tumor properties. It also activates inducible nitric oxide synthase and promotes leukocyte migration. Both, IL-2 and IFN-γ trigger macrophages to release IL-1 and tumor necrosis factor alpha. These mediators are important stimulants for generating
an inflammatory response by the body in response to infections (Fig 2). 3. Mediators (cytokines) role in sepsis11,16–19 There are two types of mediators that are released in response to infection, pro- and anti-inflammatory mediators (Table 3). It is assumed that the inflammatory response that characterizes sepsis results from excessive pro-inflammatory mediators while the compensatory anti-inflammatory reaction (CARS) fails to cause adequate immunosuppression. Similarly, if CARS is triggered in an excessive manner, immunoparalysis occurs, enabling existing infections to flare up. Pro-Inflammatory Cytokines. Macrophage stimulation causes production of large amounts of tumor necrosis factor alpha (TNF-α), interleukin 1 (IL-1), and IL-6. TNF-α is one of the most important cytokines involved in the pathophysiology of sepsis and is released early in the process. Other pro-inflammatory mediators facilitate inflammation by promoting endothelial cell–leukocyte adhesion, inducing the release of nitric oxide, arachidonic acid metabolites, and activating the complement cascade. In addition, pro-inflammatory mediators promote coagulation by increasing tissue-coagulation factor levels and membrane coagulants. They also inhibit anticoagulant activity by decreasing thrombomodulin and by inhibiting fibrinolysis. Anti-Inflammatory Cytokines. In contrast to pro-inflammatory cytokines, anti-inflammatory mediators inhibit inflammation by inhibiting TNF-α, augmenting acutephase reactants and immunoglobulins, and inhibiting T-lymphocyte functions. Anti-inflammatory mediators also inhibit activation of the coagulation system. The anti-inflammatory response serves as a negative feedback mechanism to down-regulate the synthesis of proinflammatory mediators and modulate their effects, thereby restoring homeostasis and preventing SIRS.
Phase 3: The Effects of Excessive Specific Mediators
Fig 2. Effect of exotoxin (superantigen) on release of mediators of inflammation.
i. Pro-inflammatory mediators facilitate inflammation by promoting endothelial cell–leukocyte adhesion, inducing the release of arachidonic acid metabolites and complement activation. In addition, pro-inflammatory mediators induce vasodilation by excessive production of NO,
262
Curr Probl Pediatr Adolesc Health Care, November/December 2013
TABLE 3. Mediators in sepsis
Pro-inflammatory mediators
Anti-inflammatory mediators
TNF-α IL1b, IL-2, IL-8, IL-15 Neutrophil elastase IFN-γ Thromboxane, platelet-activating factor Vasoactive neuropeptides Plasminogen activator inhibitor-1 Prostaglandins, prostacyclin Free radical generation Soluble adhesion molecules Tyrosine kinase, Protein kinase H2S, NO HMGB1 protein
IL-1Ra IL-4 IL-10 IL-13 Type II IL-1 receptor Transforming growth factor-β Epinephrine phospholipase A2 Epinephrine phospholipase A2 Soluble TNF-α receptor Leukotriene B4-receptor antagonist LPS-binding protein Soluble recombinant CD-14
Adapted with permission from Bone et al.6
they increase coagulation by an increased release of tissue factors and membrane coagulants, inhibit anticoagulant activity by decreasing thrombomodulin and inhibiting fibrinolysis. ii. In contrast, anti-inflammatory mediators inhibit inflammation by inhibiting TNF-α, augmenting acute-phase reactants and immunoglobulins, and inhibiting T-lymphocyte and macrophage functions. Anti-inflammatory mediators also inhibit activation of the coagulation system by cytokines. The anti-inflammatory response serves as a negative feedback mechanism to downregulate the synthesis of pro-inflammatory mediators, modulate their effects, and thereby restore homeostasis. iii. SIRS results from an excessive pro-inflammatory response. By contrast, an excessive compensatory anti-inflammatory reaction (CARS) results in an inappropriate immunosuppression. If an imbalance develops between SIRS and CARS, homeostasis is violated and a clinical progression towards multiorgan dysfunction may occur.
References 1. Geroulanos S, Douka ET. Historical perspective of the word ‘‘sepsis”. Intensive Care Med 2006;32:2077. 2. Vincent JL, Abraham E. The last 100 years of sepsis. Am J Respir Crit Care Med 2006;173:256–63. 3. Bone RC, Fisher CJ, Clemmer TP, et al. Sepsis syndrome: a valid clinical entity. Crit Care Med 1989;17:389–93. 4. Bone RC. Why new definitions of sepsis are needed. Am J Med 1993;95:348–50.
Curr Probl PediatrAdolesc Health Care, November/December 2013
5. Poeze M, Ramsay G, Gerlach H, et al. An international sepsis survey: a study of doctors' knowledge and perception about sepsis. Crit Care 2004;8:R409–13. 6. Bone RC, Grodzin CJ, Balk RA. Sepsis: a new hypothesis for pathogenesis of the disease process. Chest 1997;112:235–43. 7. ACCP-SCCM Consensus Conference. Definitions of sepsis and multiple organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med 1992;20:864–74. 8. Angus DC, Burgner D, Wunderink R, et al. The PIRO concept: P is for predisposition. Crit Care 2003;7(3):248–451. 9. Bone RC. The pathogenesis of sepsis. Ann Intern Med 1991;115:457–69. 10. Glauser MP, Zanetti G, Baumberger JD, Cohen J. Septic shock: pathogenesis. Lancet 1991;338:732–6. 11. Bhatia M, Moochhala S. Role of inflammatory mediators in the pathophysiology of acute respiratory distress syndrome. J Pathol 2004;202:145–56. 12. Gogos CA, Drosou E, Bassaris HP, Skoutelis A. Pro-versus anti-inflammatory cytokine profile in patients with severe sepsis: a marker for prognosis and future therapeutic options. J Infect Dis 2000;181:176–80. 13. Underhill DM, Ozinsky A. Toll-like receptors: key mediators of microbe detection. Curr Opin Immunol 2002;14:103–10. 14. Underhill DM. Toll-like receptors: networking for success. Eur J Immunol 2003;33:1767–75. 15. Vasselon T, Detmers PA. Toll receptors: a central element in innate immune responses. Infect Immun 2002;70:1033–41. 16. Evans TJ. The role of macrophages in septic shock. Immunobiology 1996;195:655–9. 17. Mathison JC, Wolfson E, Ulevitch RJ. Participation of tumor necrosis factor in the mediation of Gram negative bacterial lipopolysaccharide-induced injury in rabbits. J Clin Invest 1988;81:1925–37. 18. Tracey KJ, Cerami A. Tumor necrosis factor: a pleiotropic cytokine and therapeutic target. Annu Rev Med 1994;45: 491–503. 19. Opal SM, Cohen J. Clinical Gram-positive sepsis: does it fundamentally differ from Gram-negative bacterial sepsis? Crit Care Med 1999;27:1608–16.
263
