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Special article: The association of sepsis with multiple organ dysfunction syndrome
Special Article The Association of Sepsis With Multiple Organ Dysfunction Syndrome Maria J. Basterrechea, RD, and Fernando Stein, MD Multiple organ dysfunction syndrome (MODS), a clinical condition that involves relentless organ dysfunction accompanied by abnormal organ system interactions, is triggered primarily by sepsis and trauma. An understanding of the three basic pathophysiological processes involved (acute-phase; release of chemicals from agents responsible for infection; and interaction of substrate production, availability, and utilization in the response to injury or infection) and the factors that operate in the acute-phase response is critical for the appropriate use and development of agents to modify the chain of events leading to MODS. This article addresses the unregulated activation of the systemic inflammatory cascade, the effects of alterations of oxygen uptake and oxygen delivery relationships, and treatment approaches regarding the triggering agent, the syndrome itself, and cardiovascular failure. Copyright r 2000 by W.B. Saunders Company
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ultiple organ dysfunction syndrome (MODS) is a clinical condition that has received several different names during the last two decades. Sepsis syndrome, systemic inflammatory response syndrome (SIRS), multiple organ system failure (MOSF), and a few other nomenclatures have been used in attempts to describe a complex pathophysiological process that is associated with the majority of deaths in the intensive care unit (ICU).1 The pathogenesis of MODS is related to a progression of SIRS to MODS. Sepsis frequently is associated with MODS, but it is not an absolute prerequisite. The problems of inflammation and infection leading to MODS may contribute to mortality rates as high as 80%.2 MODS is defined as a syndrome of relentless organ dysfunction accompanied by abnormal organ system interactions, associated with two chief pathophysiological derangements: (1) the unregulated activation of systemic inflammatory cascades and (2) alterations of oxygen uptake–oxygen delivery relationships.3 The most common triggers are sepsis and trauma. Regardless of the trigger, the biological interactions are numerous. They include the host’s response to inflammation, the particular chemicals that are released by different microorganisms that may be responsible for infection, and the host’s derived inflammatory mediators that are released by cellular and systemic entities. The uncoupling of the communications between organs with evident physiological dysregulation appears to be the hallmark of the syndrome. The solution to the complex interactions that lead to MODS rests in the understanding of three basic pathophysiological
From the Department of Pediatrics, Baylor College of Medicine, Houston, TX. Address correspondence to Fernando Stein, MD, Department of Pediatrics, 6621 Fannin St, TCH MS 2-3450, Houston, TX 77030. Copyright r 2000 by W.B. Saunders Company 1045-1870/00/1101-0011$10.00/0
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processes: (1) the acute-phase response and its regulation; (2) the release of chemicals (capable of triggering the acute-phase response) from agents responsible for infection; and (3) the interaction of substrate production, availability, and utilization in the response to injury or infection. The scientific understanding of the factors that operate in the acute-phase response and the sequence in which the processes operate is essential for the appropriate use and development of agents to modify the chain of events leading to MODS. Because the blockade of inflammatory mediators may yield different clinical results from modulation at another point, the sequence may be more important than the process. The systemic response to injury is complex, and simplistic mechanistic paradigms do not adequately represent the multifaceted and sequential nature of the response. The association of infection and MODS has been well established.4 Sepsis is the systemic response to infection. Sepsis and its sequelae are stages of the progression of an illness that is the result of the macrophage-derived systemic response to infection. The cytokines released by macrophages mediate the response by targeting end-organ receptors. Sepsis is the precipitating factor in both MODS and, frequently, acute respiratory distress syndrome (ARDS). During the entire process of the body responding to infection, there are feedback mechanisms that turn on or off the production of neurohormonal substances, as well as local reactions to the inflammatory process. To succeed in its fight against infection, the human body must be able to recognize and subsequently eliminate antigen derived from the infecting organisms. The elimination of antigen must take place through a series of integrated and coordinated sequential steps. The material must be recognized as invading or ‘‘foreign’’ by antibodies or by the receptors on T lymphocytes.5 The receptors on the lymphocytes bind to specific epitopes on the antigen. The process of recognition by binding the compo-
Seminars in Pediatric Infectious Diseases, Vol 11, No 1 ( January), 2000: pp 68-72
The Association of Sepsis and MODS nent of the immune system to an antigen results in the activation of a system that amplifies the response and, consequently, initiates the proinflammatory substance production. Vascular permeability alterations occur because of alterations the proinflammatory mediators cause in the regulation of blood flow. To compound the problem, these mediators augment the adherence of circulating leukocytes to the endothelium of blood vessels and promote the migration of these white blood cells and the destruction of the attacking agents by phagocytosis. The phagocytic cells (neutrophils, eosinophils, and monocytes) are procured from both fixed tissue sites and circulating blood. In addition, nitric oxide is produced during the host reaction, generally in large quantities. Nitric oxide is produced by activated macrophages and is involved in the pathogenesis of the hyperdynamic state, septic shock, and inflammation.6 The immune processes represent a continuum, and no inflammation is detected during the normal process of antigen elimination. However, excessive inflammation as a result of severe sepsis or abnormal recognition of host tissue as ‘‘foreign’’ leads to inflammatory response disorder. Once the recognition of antigen has been completed by immunoglobulins, proteins of major histocompatibility T-cell receptors, antigen-antibody complexes are formed and can be eliminated by phagocytosis, direct lysis by products of the complement pathway, or lysis by macrophages or natural killer cells.7
Unregulated Activation of Systemic Inflammatory Cascade The presence of a robust complex immunologic cascade is indispensable as a protective reaction to the attack of microorganisms. When the process of activation and amplification is triggered, a series of potentially lethal chemicals is released as a result of an excessive or poorly regulated response.8 There are seven principal soluble components of inflammation (Table 1). Although no absolute scientifically conclusive diagram of the early biochemical events in the acute-phase response exists, information is sufficient to approximate the sequence of these events (Fig 1). A toxic stimulus triggers the production of inflammatory monokines (interleukin-1 and tumor necrosis factor). These substances cause endothelial cell adhesion of the neutrophils, generation of clotting factors, and numerous other secondary inflammatory mediators (Table 2). Antiinflammatory compounds also are released, and negative feedback to the inflammatory process occurs. The balance between upregulation and downregulation of the early biochemical events determines the pathophysiological consequences of Table 1. Soluble Components of Inflammation Immunoglobulins Complement cascade Contact activation system Lipid-derived mediators of inflammation Histamine Cytokines Nitric oxide
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Figure 1. Schematic sequence of events in sepsis. the host. After the release of the secondary mediators of inflammation, fluid escapes across the endothelial wall and microthrombosis and, depending on which mediator predominates and the endocrine response to stress, vasoconstriction or vasodilatation occur. Accompanying these responses are platelet aggregation, consumption of clotting factors, and acute cellular dysfunction in the bone in particular. A positive biological process is apoptosis. Tumor necrosis factor induces a signal transduction pathway that leads to programmed cell death or apoptosis. Apoptosis disposes of infected cells or damaged cells without triggering an inflammatory response. A disordinate propagation of activated lymphocytes could overwhelm the host if allowed to proliferate indefinitely. The immune system uses a method to control the cell population that involves the Fas ligand, a protein expressed on the surface of cytotoxic T lymphocytes.9
Alteration of Oxygen Uptake–Oxygen Delivery Relationships Shock is defined as poor delivery of oxygen to the tissues. Septic shock is inadequate oxygen delivery to the tissues as a result of failed compensatory mechanisms operating in the fight against infection. Septic shock implies an imbalance between oxygen demand and supply. Systemic oxygen demand that outstrips oxygen supply has been referred to as ‘‘oxygen debt.’’10 Currently available data show a direct correlation between the duration of oxygen debt and the subsequent development of organ failure and death.11,12 Conversely, elevation of cardiac output and oxygen delivery improves the outcome of septic shock.13 Under normal circumstances, a reduction in the delivery of oxygen or an increase in oxygen consumption will result in an increase in oxygen extraction. For reasons that are incompletely understood, patients with a variety of acute illnesses who have drastic reductions in the delivery of oxygen are unable to increase oxygen extraction. In the context of sepsis, particularly gram-negative sepsis, the cause has been ascribed to peripheral shunting or an uneven distribution of cardiac output.14 Table 2. Secondary Inflammatory Mediators Prostaglandins Cytokines Proteases Leukotrienes Prostacyclin Thromboxane Platelet-activating factor Interleukin-1
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Numerous studies document the presence of a relationship between oxygen consumption and systemic delivery that is directly proportional up to a point where consumption becomes independent of delivery (Fig 2). Optimization of oxygen delivery during septic shock is a cornerstone for both survival and minimization of individual organ damage. Individual organs can adapt oxygen extraction to very high levels by redistribution of the microcirculation. The neural regulation of blood flow during shock states is altered by the endogenous release of various catecholamines and the mediators of inflammation. Precapillary sphincter tone changes as organ oxygen delivery is altered. It can be a primary or secondary effect. If primary constriction of the precapillary sphincters occurs, a consequent decrease in oxygen delivery to the individual organ results. As organ oxygen delivery decreases, closed capillaries open, increasing perfused capillary density and allowing the organ to extract more oxygen. Increasing the capillary density causes an increase in the cross-sectional resistance of capillaries available for blood flow. This event results in a decreased flow velocity in each capillary, thus allowing more time for oxygen diffusion. The opening of capillaries that previously were closed brings blood cells closer to the tissues, and the diffusion distance decreases.
Treatment Approaches Triggering Agent The triggering agent or cause must be attacked, and the diagnosed or presumed cause that started the sequence of MODS must be identified and treated appropriately. MODS, like ARDS, is the consequence of an insult or injury, not a diagnosis in itself. A general set of principles for the possible improvement or even prevention of the progress from SIRS to MODS has been proposed by Zimmerman15 (Table 3). As mentioned earlier, the understanding of the cascade of events associated with MODS is not complete at the moment, and interventions that alter the sequence at one point can have very negative consequences at another. Antimicrobial drugs are indispensable for the treatment of sepsis and its related complications but generally are not
Figure 2. Normal relationship of total body O2 consumption to O2 delivery. The curve is directly proportional until the critical delivery of O2 is reached, and then it becomes independent. The value of critical O2 delivery that is consistently associated with survival is greater than 600 mL/min/m2.
Table 3. Prevention Strategies Against MODS 1. Improve microcirculatory blood 2. Perform early surgery as needed to limit secondary injury and infection 3. Eliminate necrotic tissue 4. Improve oxygen delivery, oxygen consumption, and individual organ blood flow 5. Support the gastrointestinal tract and provide adequate nutrition 6. Titillate host immunity with proinflammatory and antiinflammatory immunomodulation 7. Treat the patient’s related illness and not simply the mediators
sufficient. The administration of antibiotics per se can cause the unleashing of inflammatory mediators from bacterial death. The characteristic symptoms described by Jarisch16 and Herxheimer17 of fever, tachycardia, and hypotension associated with the administration of antisyphilitic agents have been observed in the treatment of other infections with various kinds of antibiotics. Data about the contribution to mortality by the initial antibiotic doses are imprecise. Most pediatric intensivists have the common experience of having patients deteriorate severely after the initial administration of antibiotics in the case of severe sepsis. The incidence has been reported to be up to 5 percent. As a result, attempts to control this type of reaction by treating with antibodies against tumor necrosis factor-␣ have been reported.18 Treating with antibiotics promptly is necessary, and starting empiric treatment with broad-spectrum antibiotics until the causative organisms are identified and the antibiotic treatment is narrowed is recommended.
Multiple Organ Dysfunction Syndrome The treatment of MODS is supportive with special attention directed to the individual organs affected. Supportive intensive care is responsible for most of the improvements in both morbidity and mortality. Adequate restoration to the intact system of oxygen transport and delivery and the delivery of adequate substrate and utilization at a cellular level are the ultimate therapeutic goals. The most pronounced hemodynamic features of septic shock are decreased peripheral substrate utilization (oxygen and other nutrients) and low systemic vascular resistance. As noted above, distribution of flow in the individual organ is uneven, with some vascular beds constricted and others dilated. The combination of these phenomena with the aggregation of platelets and neutrophils reduces blood flow. Margination ensues, resulting in the release of the many mediators of inflammation and the migration of neutrophils into the tissues. Oxygen species are released by neutrophils that produce direct cellular damage, and the components of the complement system are activated. Inflammatory mediators can cause local vasodilatation or vasoconstriction. The numerous mediators and inflammatory cells causing alterations of blood flow eventually lead to poor capillary perfusion, which is but one of the principal players in organ failure. Hypoperfusion causes a shift to anaerobic metabolism, with a resultant drop in tissue pH and the accumulation of nitrogenous bodies. In addition, this decrease of blood flow
The Association of Sepsis and MODS decreases the tissue stores of high-energy phosphorylated compounds. The organs that classically are affected after severe sepsis are the lungs, the heart, the kidneys, the gastrointestinal system, and the hematopoietic system. Although the central nervous system can be affected, it usually is a late complication and the result of the accumulated effects of hypotension, hypoxemia, or reperfusion injury. The mortality of patients who have two of these organs fail during sepsis is close to 40 percent.19 The risk of mortality increases by 15 to 20 percent with each individual organ failure.
Treatment of Cardiovascular Failure Myocardial depression and its consequent cardiovascular failure are mediated by two main mechanisms. The first is myocardial depression from direct and indirect effect of circulating substances, such as endotoxin, tumor necrosis factor-␣, and endorphins. The second is myocardial depression from impaired coronary blood flow. This mechanism has been measured in humans during septic shock.20 Shock associated with sepsis is a complex syndrome that has several phases in its progression. They are not clearly defined and overlap during the course of the illness. Septic shock encompasses myocardial depression, blood flow maldistribution, and hypovolemia. A carefully preconceived plan of monitoring and intervention includes the understanding of the physiological changes that are the normal reaction to sepsis and the control of these reactions to a point. For example, overaggressive administration of fluid and early shock will result in decreased systemic vascular resistance and, if the myocardium has not been severely depressed, hyperdynamic shock syndrome.21 Support of the circulation with volume and sympathomimetic amines definitely is the mainstay of therapy, and it is safe and effective in most cases. Occasionally, patients can have such severe myocardial dysfunction that the use of mechanical support of the circulation is warranted. The outcome of this type of intervention is favorable when the patients do not have ARDS in addition. The outcome of patients who have both cardiac and pulmonary failure and for whom conventional therapies do not succeed is very poor. Cardiac output can be low, normal, or increased during septic shock, even in the presence of abnormal ventricular function. Echocardiography during septic shock has documented ventricular dysfunction in most cases. The use of invasive hemodynamic measurements for the purposes of adjusting therapy in children is imprecise and should be undertaken in the context of the entire clinical situation. The use of pulmonary artery flotation catheters with oxymetric capabilities is useful for the calculations and measurements of oxygen consumption, delivery, systemic vascular resistance, and, especially, pulmonary artery wedge pressure. These calculations are useful in adjusting sympathomimetic drug combinations and intravascular volume assessment and administration.
Treatment of Pulmonary Failure As is the case with the cardiovascular system, the substances that exert deleterious effects on the heart and vessels affect
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Table 4. Diagnostic Criteria for ARDS in Children 1. Acute and rapidly progressive pulmonary dysfunction of noncardiac origin 2. Diffuse bilateral pulmonary infiltrates on chest radiographs 3. Arterial oxygen to fraction of inspired oxygen of less than 150 without the use of positive end-expiratory pressure (PEEP) or less than 200 with the use of PEEP 4. Pulmonary artery occlusion pressure less than 18 mm Hg (optional) the lung. Some other mechanisms affect the alveolar units and pulmonary homeostasis very directly. ARDS is the clinical presentation that is the most common form of pulmonary failure in association with sepsis. It is bilateral and diffuse and includes reduced lung compliance and hypoxemia (Table 4). The pathological findings in the lungs of patients with ARDS explain the clinical picture. Edematous hyaline membrane formation is the most common and generic finding. Pulmonary edema is a result of low vascular pressure, which in turn is the result of various local and systemic factors that mediate capillary leak.22 The radiograph findings are, therefore, predictable. During the first 3 to 6 days, edematous alveolar interstitial changes dominate the microscopic findings. After this period, a process of repair, which involves cellular proliferation and eventual fibrosis, occurs.23 From the management standpoint, conventional methods of ventilatory support are safe and effective for most survivors of ARDS. The ‘‘styles’’ of mechanical ventilation vary considerably around the country, but some general principles are widely accepted (Table 5). Most of the sequelae of ARDS are the result of mechanical ventilation. The strategies outlined in Table 5 are aimed at minimizing iatrogenic lung injury. Secondary lung injury is the result of oxygen toxicity, barotrauma, and the process of lung injury repair with fibrosis. The use of extracorporeal membrane oxygenation in ARDS remains controversial. The difficulty in standardizing indications and severity of illness, combined with the timing of intervention, renders the studies difficult to interpret. Highfrequency oscillation ventilation, liquid ventilation, and highfrequency jet ventilation are being used in different centers around the country. Because most patients do not require these levels of intervention, scientifically conclusive information is not available at this time. Of all of the nonconventional methods of Table 5. Principles of Ventilatory Support in ARDS 1. Permit hypercarbia 2. Minimize mean airway pressure while maintaining oxygenation 3. Use PEEP early to keep FiO2 less than 60% 4. Maintain optimal lung volume throughout the respiratory cycle without overdistending at peak pressure 5. Minimize accumulation of lung water 6. Treat and prevent nosocomial pneumonia 7. Treat the underlying cause of ARDS
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ventilation, the high-frequency oscillation ventilation shows the greatest promise in terms of minimizing secondary lung injury. Liquid ventilation is being investigated.
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References
13.
1. Livingstone DH, Mosenthal AC, Deitch EA: Sepsis and multiple organ dysfunction syndrome: A clinical-mechanistic overview. New Horizons 3:257-266, 1995 2. Baue AE, Durham R, Faist E: Systemic inflammatory response syndrome (SIRS), multiple organ dysfunction syndrome (MODS), multiple organ failure (MOF): Are we winning the battle? Shock 10:79-89, 1998 3. McClave SA, Snider HL: Understanding the methodological response to critical illness: Factors that cause patients to deviate from the expected pattern of hypermetabolism. New Horizons 2:175-185, 1994 4. Bone RC, Gordzin CJ, Balk RA: Sepsis: A new hypothesis for pathogenesis of the disease process. Chest 12:235-243, 1997 5. Mariscalco MM: Infection and the host response, in Furman BP, Ziemmerman JJ (eds): Pediatric Critical Care (ed 2). St Louis, MO, Mosby, 1998, pp 979-994 6. Moncada S, Higgs A: The L-arginine-nitric oxide pathway. N Engl J Med 329:2002-2012, 1993 7. Williams AF, Barclay AN: The immunoglobulin superfamily, domains for cell surface recognition. Ann Rev Immunol 6:381, 1988 8. Wheeler AP, Bernard GR: Treating patients with severe sepsis. N Engl J Med 340:207-214, 1999 9. Eischen CM, Leibeson PJ: Roll of NK-cell associated Fas-ligand in cell mediated cytotoxicity and apoptosis. Res Immunol 148:164-169, 1997 10. Shoemaker WC, Appel PL, Kram HB: Role of oxygen debt in the development of organ failure sepsis, and death in high risk surgical patients. Chest 102:208-215, 1992 11. Russell JH, Ronco JJ, Lockhat D, et al: Oxygen delivery in patients
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with adult respiratory distress syndrome who undergo surgery. Arch Surg Respir 141:659-665, 1990 Edwards JD, Brown GCS, Nightingale P: Use of survivors’ cardiorespiratory values as therapeutic goals in septic shock. Crit Care Med 17:1098-1103, 1989 Tuchschmitd J, Fried J, Astiz A, et al: Elevation of cardiac output and oxygen delivery improves outcome in septic shock. Chest 102:216-220, 1992 Mani J, Justice R, Hechtman HB: Abnormalities in normal blood flow and its distribution during positive end expiratory pressure. Surgery 85:4-25, 1997 Zimmerman JJ: Sepsis/septic shock, in Furman BP, Ziemmerman JJ (eds): Pediatric Critical Care (ed 2). St Louis, MO, Mosby, 1998, pp 1088-1100 Jarisch A: Therapeutisch Versuche bei Syphilis. Wein Med Wochenschr 45:721-724, 1895 Herxheimer K: Uber ein bei Syphiltischen Vorkommende Queksilberreaktion. Dtsch Med Wochenschr 28:895-897, 1902 Fekade D, Knox K, Hussein K, et al: Prevention of JarischHerxheimer reactions by treatment with antibodies against tumor necrosis factor-alpha. N Engl J Med 335:311-315, 1996 Pittet D, Thiebent B, Wenzel NP, et al: Bedside prediction of mortality from bacteremic sepsis: A dynamic analysis of ICU patients. Am J Respir Crit Care Med 153:684-693, 1996 Cunniun RE, Schar GL, Parker MM, et al: The coronary circulation in human septic shock. Circulation 73:637-644, 1986 Parker MM, McCarthy KE, Ognibene FP, et al: Right ventricular dysfunction and dilatation, similar to left ventricular changes, characterize the cardiac depression of septic shock in humans. Chest 97:126-131, 1990 Paulson TE, Spear RM, Peterson BM: New concepts in the treatment of children with acute respiratory distress syndrome. J Pediatr 127:163-175, 1995 Tomashefsky JF: Pulmonary pathology of the adult respiratory distress syndrome. Clin Chest Med 11:593-619, 1990
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ultiple organ dysfunction syndrome (MODS) is a clinical condition that has received several different names during the last two decades. Sepsis syndrome, systemic inflammatory response syndrome (SIRS), multiple organ system failure (MOSF), and a few other nomenclatures have been used in attempts to describe a complex pathophysiological process that is associated with the majority of deaths in the intensive care unit (ICU).1 The pathogenesis of MODS is related to a progression of SIRS to MODS. Sepsis frequently is associated with MODS, but it is not an absolute prerequisite. The problems of inflammation and infection leading to MODS may contribute to mortality rates as high as 80%.2 MODS is defined as a syndrome of relentless organ dysfunction accompanied by abnormal organ system interactions, associated with two chief pathophysiological derangements: (1) the unregulated activation of systemic inflammatory cascades and (2) alterations of oxygen uptake–oxygen delivery relationships.3 The most common triggers are sepsis and trauma. Regardless of the trigger, the biological interactions are numerous. They include the host’s response to inflammation, the particular chemicals that are released by different microorganisms that may be responsible for infection, and the host’s derived inflammatory mediators that are released by cellular and systemic entities. The uncoupling of the communications between organs with evident physiological dysregulation appears to be the hallmark of the syndrome. The solution to the complex interactions that lead to MODS rests in the understanding of three basic pathophysiological
From the Department of Pediatrics, Baylor College of Medicine, Houston, TX. Address correspondence to Fernando Stein, MD, Department of Pediatrics, 6621 Fannin St, TCH MS 2-3450, Houston, TX 77030. Copyright r 2000 by W.B. Saunders Company 1045-1870/00/1101-0011$10.00/0
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processes: (1) the acute-phase response and its regulation; (2) the release of chemicals (capable of triggering the acute-phase response) from agents responsible for infection; and (3) the interaction of substrate production, availability, and utilization in the response to injury or infection. The scientific understanding of the factors that operate in the acute-phase response and the sequence in which the processes operate is essential for the appropriate use and development of agents to modify the chain of events leading to MODS. Because the blockade of inflammatory mediators may yield different clinical results from modulation at another point, the sequence may be more important than the process. The systemic response to injury is complex, and simplistic mechanistic paradigms do not adequately represent the multifaceted and sequential nature of the response. The association of infection and MODS has been well established.4 Sepsis is the systemic response to infection. Sepsis and its sequelae are stages of the progression of an illness that is the result of the macrophage-derived systemic response to infection. The cytokines released by macrophages mediate the response by targeting end-organ receptors. Sepsis is the precipitating factor in both MODS and, frequently, acute respiratory distress syndrome (ARDS). During the entire process of the body responding to infection, there are feedback mechanisms that turn on or off the production of neurohormonal substances, as well as local reactions to the inflammatory process. To succeed in its fight against infection, the human body must be able to recognize and subsequently eliminate antigen derived from the infecting organisms. The elimination of antigen must take place through a series of integrated and coordinated sequential steps. The material must be recognized as invading or ‘‘foreign’’ by antibodies or by the receptors on T lymphocytes.5 The receptors on the lymphocytes bind to specific epitopes on the antigen. The process of recognition by binding the compo-
Seminars in Pediatric Infectious Diseases, Vol 11, No 1 ( January), 2000: pp 68-72
The Association of Sepsis and MODS nent of the immune system to an antigen results in the activation of a system that amplifies the response and, consequently, initiates the proinflammatory substance production. Vascular permeability alterations occur because of alterations the proinflammatory mediators cause in the regulation of blood flow. To compound the problem, these mediators augment the adherence of circulating leukocytes to the endothelium of blood vessels and promote the migration of these white blood cells and the destruction of the attacking agents by phagocytosis. The phagocytic cells (neutrophils, eosinophils, and monocytes) are procured from both fixed tissue sites and circulating blood. In addition, nitric oxide is produced during the host reaction, generally in large quantities. Nitric oxide is produced by activated macrophages and is involved in the pathogenesis of the hyperdynamic state, septic shock, and inflammation.6 The immune processes represent a continuum, and no inflammation is detected during the normal process of antigen elimination. However, excessive inflammation as a result of severe sepsis or abnormal recognition of host tissue as ‘‘foreign’’ leads to inflammatory response disorder. Once the recognition of antigen has been completed by immunoglobulins, proteins of major histocompatibility T-cell receptors, antigen-antibody complexes are formed and can be eliminated by phagocytosis, direct lysis by products of the complement pathway, or lysis by macrophages or natural killer cells.7
Unregulated Activation of Systemic Inflammatory Cascade The presence of a robust complex immunologic cascade is indispensable as a protective reaction to the attack of microorganisms. When the process of activation and amplification is triggered, a series of potentially lethal chemicals is released as a result of an excessive or poorly regulated response.8 There are seven principal soluble components of inflammation (Table 1). Although no absolute scientifically conclusive diagram of the early biochemical events in the acute-phase response exists, information is sufficient to approximate the sequence of these events (Fig 1). A toxic stimulus triggers the production of inflammatory monokines (interleukin-1 and tumor necrosis factor). These substances cause endothelial cell adhesion of the neutrophils, generation of clotting factors, and numerous other secondary inflammatory mediators (Table 2). Antiinflammatory compounds also are released, and negative feedback to the inflammatory process occurs. The balance between upregulation and downregulation of the early biochemical events determines the pathophysiological consequences of Table 1. Soluble Components of Inflammation Immunoglobulins Complement cascade Contact activation system Lipid-derived mediators of inflammation Histamine Cytokines Nitric oxide
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Figure 1. Schematic sequence of events in sepsis. the host. After the release of the secondary mediators of inflammation, fluid escapes across the endothelial wall and microthrombosis and, depending on which mediator predominates and the endocrine response to stress, vasoconstriction or vasodilatation occur. Accompanying these responses are platelet aggregation, consumption of clotting factors, and acute cellular dysfunction in the bone in particular. A positive biological process is apoptosis. Tumor necrosis factor induces a signal transduction pathway that leads to programmed cell death or apoptosis. Apoptosis disposes of infected cells or damaged cells without triggering an inflammatory response. A disordinate propagation of activated lymphocytes could overwhelm the host if allowed to proliferate indefinitely. The immune system uses a method to control the cell population that involves the Fas ligand, a protein expressed on the surface of cytotoxic T lymphocytes.9
Alteration of Oxygen Uptake–Oxygen Delivery Relationships Shock is defined as poor delivery of oxygen to the tissues. Septic shock is inadequate oxygen delivery to the tissues as a result of failed compensatory mechanisms operating in the fight against infection. Septic shock implies an imbalance between oxygen demand and supply. Systemic oxygen demand that outstrips oxygen supply has been referred to as ‘‘oxygen debt.’’10 Currently available data show a direct correlation between the duration of oxygen debt and the subsequent development of organ failure and death.11,12 Conversely, elevation of cardiac output and oxygen delivery improves the outcome of septic shock.13 Under normal circumstances, a reduction in the delivery of oxygen or an increase in oxygen consumption will result in an increase in oxygen extraction. For reasons that are incompletely understood, patients with a variety of acute illnesses who have drastic reductions in the delivery of oxygen are unable to increase oxygen extraction. In the context of sepsis, particularly gram-negative sepsis, the cause has been ascribed to peripheral shunting or an uneven distribution of cardiac output.14 Table 2. Secondary Inflammatory Mediators Prostaglandins Cytokines Proteases Leukotrienes Prostacyclin Thromboxane Platelet-activating factor Interleukin-1
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Numerous studies document the presence of a relationship between oxygen consumption and systemic delivery that is directly proportional up to a point where consumption becomes independent of delivery (Fig 2). Optimization of oxygen delivery during septic shock is a cornerstone for both survival and minimization of individual organ damage. Individual organs can adapt oxygen extraction to very high levels by redistribution of the microcirculation. The neural regulation of blood flow during shock states is altered by the endogenous release of various catecholamines and the mediators of inflammation. Precapillary sphincter tone changes as organ oxygen delivery is altered. It can be a primary or secondary effect. If primary constriction of the precapillary sphincters occurs, a consequent decrease in oxygen delivery to the individual organ results. As organ oxygen delivery decreases, closed capillaries open, increasing perfused capillary density and allowing the organ to extract more oxygen. Increasing the capillary density causes an increase in the cross-sectional resistance of capillaries available for blood flow. This event results in a decreased flow velocity in each capillary, thus allowing more time for oxygen diffusion. The opening of capillaries that previously were closed brings blood cells closer to the tissues, and the diffusion distance decreases.
Treatment Approaches Triggering Agent The triggering agent or cause must be attacked, and the diagnosed or presumed cause that started the sequence of MODS must be identified and treated appropriately. MODS, like ARDS, is the consequence of an insult or injury, not a diagnosis in itself. A general set of principles for the possible improvement or even prevention of the progress from SIRS to MODS has been proposed by Zimmerman15 (Table 3). As mentioned earlier, the understanding of the cascade of events associated with MODS is not complete at the moment, and interventions that alter the sequence at one point can have very negative consequences at another. Antimicrobial drugs are indispensable for the treatment of sepsis and its related complications but generally are not
Figure 2. Normal relationship of total body O2 consumption to O2 delivery. The curve is directly proportional until the critical delivery of O2 is reached, and then it becomes independent. The value of critical O2 delivery that is consistently associated with survival is greater than 600 mL/min/m2.
Table 3. Prevention Strategies Against MODS 1. Improve microcirculatory blood 2. Perform early surgery as needed to limit secondary injury and infection 3. Eliminate necrotic tissue 4. Improve oxygen delivery, oxygen consumption, and individual organ blood flow 5. Support the gastrointestinal tract and provide adequate nutrition 6. Titillate host immunity with proinflammatory and antiinflammatory immunomodulation 7. Treat the patient’s related illness and not simply the mediators
sufficient. The administration of antibiotics per se can cause the unleashing of inflammatory mediators from bacterial death. The characteristic symptoms described by Jarisch16 and Herxheimer17 of fever, tachycardia, and hypotension associated with the administration of antisyphilitic agents have been observed in the treatment of other infections with various kinds of antibiotics. Data about the contribution to mortality by the initial antibiotic doses are imprecise. Most pediatric intensivists have the common experience of having patients deteriorate severely after the initial administration of antibiotics in the case of severe sepsis. The incidence has been reported to be up to 5 percent. As a result, attempts to control this type of reaction by treating with antibodies against tumor necrosis factor-␣ have been reported.18 Treating with antibiotics promptly is necessary, and starting empiric treatment with broad-spectrum antibiotics until the causative organisms are identified and the antibiotic treatment is narrowed is recommended.
Multiple Organ Dysfunction Syndrome The treatment of MODS is supportive with special attention directed to the individual organs affected. Supportive intensive care is responsible for most of the improvements in both morbidity and mortality. Adequate restoration to the intact system of oxygen transport and delivery and the delivery of adequate substrate and utilization at a cellular level are the ultimate therapeutic goals. The most pronounced hemodynamic features of septic shock are decreased peripheral substrate utilization (oxygen and other nutrients) and low systemic vascular resistance. As noted above, distribution of flow in the individual organ is uneven, with some vascular beds constricted and others dilated. The combination of these phenomena with the aggregation of platelets and neutrophils reduces blood flow. Margination ensues, resulting in the release of the many mediators of inflammation and the migration of neutrophils into the tissues. Oxygen species are released by neutrophils that produce direct cellular damage, and the components of the complement system are activated. Inflammatory mediators can cause local vasodilatation or vasoconstriction. The numerous mediators and inflammatory cells causing alterations of blood flow eventually lead to poor capillary perfusion, which is but one of the principal players in organ failure. Hypoperfusion causes a shift to anaerobic metabolism, with a resultant drop in tissue pH and the accumulation of nitrogenous bodies. In addition, this decrease of blood flow
The Association of Sepsis and MODS decreases the tissue stores of high-energy phosphorylated compounds. The organs that classically are affected after severe sepsis are the lungs, the heart, the kidneys, the gastrointestinal system, and the hematopoietic system. Although the central nervous system can be affected, it usually is a late complication and the result of the accumulated effects of hypotension, hypoxemia, or reperfusion injury. The mortality of patients who have two of these organs fail during sepsis is close to 40 percent.19 The risk of mortality increases by 15 to 20 percent with each individual organ failure.
Treatment of Cardiovascular Failure Myocardial depression and its consequent cardiovascular failure are mediated by two main mechanisms. The first is myocardial depression from direct and indirect effect of circulating substances, such as endotoxin, tumor necrosis factor-␣, and endorphins. The second is myocardial depression from impaired coronary blood flow. This mechanism has been measured in humans during septic shock.20 Shock associated with sepsis is a complex syndrome that has several phases in its progression. They are not clearly defined and overlap during the course of the illness. Septic shock encompasses myocardial depression, blood flow maldistribution, and hypovolemia. A carefully preconceived plan of monitoring and intervention includes the understanding of the physiological changes that are the normal reaction to sepsis and the control of these reactions to a point. For example, overaggressive administration of fluid and early shock will result in decreased systemic vascular resistance and, if the myocardium has not been severely depressed, hyperdynamic shock syndrome.21 Support of the circulation with volume and sympathomimetic amines definitely is the mainstay of therapy, and it is safe and effective in most cases. Occasionally, patients can have such severe myocardial dysfunction that the use of mechanical support of the circulation is warranted. The outcome of this type of intervention is favorable when the patients do not have ARDS in addition. The outcome of patients who have both cardiac and pulmonary failure and for whom conventional therapies do not succeed is very poor. Cardiac output can be low, normal, or increased during septic shock, even in the presence of abnormal ventricular function. Echocardiography during septic shock has documented ventricular dysfunction in most cases. The use of invasive hemodynamic measurements for the purposes of adjusting therapy in children is imprecise and should be undertaken in the context of the entire clinical situation. The use of pulmonary artery flotation catheters with oxymetric capabilities is useful for the calculations and measurements of oxygen consumption, delivery, systemic vascular resistance, and, especially, pulmonary artery wedge pressure. These calculations are useful in adjusting sympathomimetic drug combinations and intravascular volume assessment and administration.
Treatment of Pulmonary Failure As is the case with the cardiovascular system, the substances that exert deleterious effects on the heart and vessels affect
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Table 4. Diagnostic Criteria for ARDS in Children 1. Acute and rapidly progressive pulmonary dysfunction of noncardiac origin 2. Diffuse bilateral pulmonary infiltrates on chest radiographs 3. Arterial oxygen to fraction of inspired oxygen of less than 150 without the use of positive end-expiratory pressure (PEEP) or less than 200 with the use of PEEP 4. Pulmonary artery occlusion pressure less than 18 mm Hg (optional) the lung. Some other mechanisms affect the alveolar units and pulmonary homeostasis very directly. ARDS is the clinical presentation that is the most common form of pulmonary failure in association with sepsis. It is bilateral and diffuse and includes reduced lung compliance and hypoxemia (Table 4). The pathological findings in the lungs of patients with ARDS explain the clinical picture. Edematous hyaline membrane formation is the most common and generic finding. Pulmonary edema is a result of low vascular pressure, which in turn is the result of various local and systemic factors that mediate capillary leak.22 The radiograph findings are, therefore, predictable. During the first 3 to 6 days, edematous alveolar interstitial changes dominate the microscopic findings. After this period, a process of repair, which involves cellular proliferation and eventual fibrosis, occurs.23 From the management standpoint, conventional methods of ventilatory support are safe and effective for most survivors of ARDS. The ‘‘styles’’ of mechanical ventilation vary considerably around the country, but some general principles are widely accepted (Table 5). Most of the sequelae of ARDS are the result of mechanical ventilation. The strategies outlined in Table 5 are aimed at minimizing iatrogenic lung injury. Secondary lung injury is the result of oxygen toxicity, barotrauma, and the process of lung injury repair with fibrosis. The use of extracorporeal membrane oxygenation in ARDS remains controversial. The difficulty in standardizing indications and severity of illness, combined with the timing of intervention, renders the studies difficult to interpret. Highfrequency oscillation ventilation, liquid ventilation, and highfrequency jet ventilation are being used in different centers around the country. Because most patients do not require these levels of intervention, scientifically conclusive information is not available at this time. Of all of the nonconventional methods of Table 5. Principles of Ventilatory Support in ARDS 1. Permit hypercarbia 2. Minimize mean airway pressure while maintaining oxygenation 3. Use PEEP early to keep FiO2 less than 60% 4. Maintain optimal lung volume throughout the respiratory cycle without overdistending at peak pressure 5. Minimize accumulation of lung water 6. Treat and prevent nosocomial pneumonia 7. Treat the underlying cause of ARDS
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ventilation, the high-frequency oscillation ventilation shows the greatest promise in terms of minimizing secondary lung injury. Liquid ventilation is being investigated.
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References
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