Advances in Treating Patients With Severe Sepsis

A trial of drotrecogin alfa (activated) has resulted in the first successful outcome in reducing mortality rates in severe sepsis. Because critical care nurses will be directly involved with the administration of drotrecogin alfa (activated) to patients with severe sepsis, knowledge of the preparation, infusion, and monitoring of the drug, presented in this article, is essential.Sepsis is a complex process that continues to pose a challenge in critical care. Despite advances in the management of infectious disease, the inability to successfully treat sepsis remains an unsolved clinical problem. Sepsis with acute organ dysfunction (severe sepsis) is common, often fatal, and expensive to treat. Each year, approximately 215000 deaths are due to severe sepsis.1 This number is virtually identical to the number of persons in the United States who die suddenly of coronary heart disease without being hospitalized and exceeds the number of deaths due to breast cancer by a factor of 4.2The increase in the incidence of severe sepsis is expected to exceed the growth of the US population well into the middle of this century. As discussed in the following, several factors contribute to this increase.3 Severe sepsis is associated with a mortality rate of 28% to 50%, percentages that are unacceptable when advances in the understanding of infectious disease and the patho-physiology of severe sepsis are considered. Additionally, the cost of treating patients with severe sepsis is estimated to be more than $16 billion per year.1Treatment with drotrecogin alfa (activated), trade name Xigris, was recently approved by the Food and Drug Administration for reduction of mortality in adult patients with severe sepsis who have a high risk of death (eg, as determined by scores on the Acute Physiology and Chronic Health Evaluation II). Critical care nurses should be familiar with this novel therapy in order to facilitate its transition into critical care practice. In this article, information is provided on the pathophysiological changes associated with severe sepsis, the use of drotrecogin alfa (activated) for patients with severe sepsis, and issues related to nursing care for patients with severe sepsis who are receiving this new therapy.In the United States, severe sepsis is the most common cause of death in noncardiac intensive care units and is the 10th leading cause of death overall.4,5 Recent data1 from an observational cohort study of all nonfederal hospitals in 7 states indicate that more than 750000 cases of severe sepsis occur each year in the United States. This number translates into an incidence of 3.0 cases per 1000 population and 2.26 cases per 100 hospital discharges.1 The incidence of sepsis is increasing because of several factors (Table 1). An important issue in estimating the number of cases of sepsis is that until recently, no diagnostic classification code existed for sepsis, only for septicemia. Because only approximately 30% of all patients with sepsis have blood cultures positive for microorganisms, cases classified as septicemia do not accurately reflect the true numbers of patients who have sepsis.6 The creation of diagnostic classification codes for severe sepsis and systemic inflammatory response syndrome (SIRS) will enhance recognition of the diseases and lead to a more accurate estimate of the prevalence of sepsis.The diagnosis of sepsis is based on a variety of clinical and physiological signs and symptoms in addition to the results of diagnostic and laboratory tests. Changes in vital signs may be the first indication of an infectious process, with elevated body temperature and increased heart rate or respiratory rate occurring as subtle but key indicators of potential sepsis. Other clinical signs, including decreased skin perfusion, decreased urine output, and central nervous system alterations (eg, confusion, agitation, lethargy), may also be present. Suspicious wound drainage, redness or swelling at the insertion sites of catheters, and cloudy or foul-smelling urine may also be clinical evidence of a possible infection. Results of diagnostic and laboratory tests, including abnormal findings on chest radiographs, elevated white blood cell count, and cultures positive for microorganisms, can provide evidence of infection. Cultures of blood, sputum, urine, or wound material may not indicate a causative organism. For 20% to 30% of patients with sepsis, a definite site of infection is not determined.6Detection of clinical indications of infection and timely initiation of diagnostic tests are important components in the early diagnosis of sepsis. The role of critical care nurses in detecting sepsis is important, because astute observation and assessment of patients can result in early and prompt diagnosis and treatment, with a subsequent decrease in sepsis-related mortality.To assist clinicians and researchers, the American College of Chest Physicians/Society of Critical Care Medicine Consensus Committee agreed on a set of definitions that can be applied to patients with sepsis and its sequelae7,8 (Table 2). The purpose of providing the definitions was to create a universal language to facilitate communication about and diagnosis of sepsis and organ failure, because terms related to sepsis were being used interchangeably.Sepsis is defined as SIRS caused by infection and is distinguished from other conditions, such as pancreatitis, that may result in SIRS. Recognizing that sepsis and its sequelae are a heterogeneous group of disorders with variable clinical and pathophysiological severities, the consensus committee defined severe sepsis as sepsis associated with acute organ dysfunction, hypoperfusion, or hypotension.Although these criteria have provided a framework for communication and investigation of sepsis and its sequelae, they have been criticized as being overly sensitive and not specific.9 In addition, they do not address the basic pathophysiology of the process. Consequently, a committee of representatives of the Society of Critical Care Medicine and the American College of Chest Physicians met in late 2001 to reevaluate and update the criteria. As a result, an expanded list of signs and symptoms (Table 3) was created to facilitate recognition of sepsis.10Severe sepsis is associated with 3 integrated responses: activation of inflammation, activation of coagulation, and impairment of fibrinolysis. These 3 responses are due to a variety of proinflammatory mediators, procoagulant factors, and inhibitors of fibrinolysis. Understanding the pathophysiology of severe sepsis and the network of cascading events that occur is important for critical care nurses as they assess and manage patients with severe sepsis.Inflammation is the body’s normal response to infection. In response to infectious organisms and their products, white blood cells, specifically monocytes and macrophages, generate and release cytokines, proteins that act as nonspecific mediators of inflammation. Inflammatory cytokines, including tumor necrosis factor-α, interleukin-1 (IL-1), IL-6, and platelet-activating factor, are released.11 Although these early-response cytokines play a critical role in host defense by attracting activated neutrophils to the site of infection, the entry of these cytokines and the products of pathogens into the systemic circulation is also associated with clinical manifestations of SIRS. As part of the host’s attempt to reestablish homeostasis, anti-inflammatory cytokines such as IL-4 and IL-10 are also released.11 Release of both proinflammatory and anti-inflammatory cytokines may lead to a state of immune refractoriness.12 In sepsis, continued activation of proinflammatory cytokines overwhelms the actions of counteractive anti-inflammatory cytokines, and excessive systemic inflammation results, contributing to impaired tissue function and organ damage.Several mechanisms activate the hemostatic pathway in patients with severe sepsis. Inflammation and coagulation are closely linked. The proinflammatory cytokines IL-1 and tumor necrosis factor-α stimulate the release of tissue factor, a cell-surface glycoprotein, from monocytes and endothelial cells. Tissue factor directly stimulates the extrinsic coagulation pathway. Stimulation of the intrinsic pathway can also occur in sepsis through cross-talk and feedback mechanisms.13 Regardless of the initiating pathway of coagulation, the result is the formation of the enzyme thrombin, which converts fibrinogen to fibrin, producing a clot (Figure 1).A state of enhanced coagulation occurs in sepsis not only through stimulation of the coagulation cascade but also through a reduction in the levels of protein C and antithrombin III, which are components of the normal anticoagulation system. These events lead to an attenuation in anticoagulant function, resulting in the generation of thrombin and a procoagulant state.13 Continued formation of thrombin leads to a prothrombotic diathesis with formation of microthrombi, which can impair blood flow and organ perfusion.Alterations in coagulation that occur in sepsis can lead to sepsis-associated coagulopathy and death. The association between activation of coagulation and severe sepsis was delineated more than 30 years ago in patients with septic shock.14 Activation of coagulation is independent of the type of infectious microorganism; gram-positive bacteria, gram-negative bacteria, fungi, and parasites all can trigger this response. The sepsis-associated coagulopathy meets the criteria of overt disseminated intravascular coagulation in less than 20% of patients. However, a prothrombotic diathesis is almost universal in patients with severe sepsis. For example, in the Effects of Ibuprofen on the Physiology and Survival of Patients With Sepsis trial,15 depressed concentrations of protein C and increased levels of D-dimers were detected in almost all enrollees. Abnormalities in fibrinolysis are also common in patients with sepsis.16–18 Thrombocytopenia can also occur and is often due to disseminated intravascular coagulation, inhibition of thrombopoiesis, or increased destruction or margination of activated platelets into the peripheral circulation.19 Laboratory markers that indicate activation of the coagulation system include D-dimers and thrombin-antithrombin complexes. In a study17 of patients with sepsis and septic shock, concentrations of markers of coagulopathy and the ratio of thrombin-antithrombin to plasminogen-antiplasmin were higher in nonsurvivors than in survivors.As part of the body’s normal response to activation of the coagulation pathway, fibrinolysis is activated concurrently to promote clot breakdown (Figure 1). In sepsis, activation of the fibrinolytic system is followed by inhibition of the system because of the release of several mediators that suppress fibrinolysis. These include plasminogen activator inhibitor-1 and thrombin activatable fibrinolysis inhibitor. Plasminogen activator inhibitor-1 is produced by endothelial cells and platelets and is the major inhibitor of tissue plasminogen activator, which normally promotes the conversion of plasminogen to plasmin to break down clots. Although plasminogen activator inhibitor-1 and thrombin activatable fibrinolysis inhibitor have a protective function in limiting excessive fibrinolysis, increased levels of these 2 inhibitors suppress fibrinolysis to the point of creating a state of coagulopathy.The imbalance between inflammation, coagulation, and fibrinolysis that occurs in severe sepsis results in systemic inflammation, widespread coagulopathy, and microvascular thrombosis, conditions that can lead to multiple organ dysfunction.The endothelium is situated at the junction of the interface between the flowing blood and the extracellular space; it influences thrombosis and antithrombosis, cell trafficking, and microcirculatory blood flow.20 Previously, the endothelium was considered an inert layer that merely separated the blood and underlying tissue.13 It has become increasingly clear that the endothelium is a metabolically active organ with an important role in many homeostatic processes, including control of vasomotor tone, promotion of movement of cells and nutrients, and maintenance of blood fluidity.13 The endothelium plays a key role in the inflammatory, prothrombotic, and impaired fibrinolytic components of sepsis. With a surface area estimated to exceed 1000 m2, the endothelium is the largest organ in the body, than the The endothelium is a organ that is by a variety of and normal endothelium has an anticoagulant In sepsis, to the endothelium occurs when proinflammatory mediators are from monocytes and to infection (Figure 2). Although the release of mediators promotes of neutrophils and of platelets to a site of infection, continued release of cytokines can result in endothelial endothelial cells may the and of such as endothelial cell for protein and tissue factor pathway the endothelium only levels of such as of these can promote between the white blood cells, and This can promote of at the site of and promote of (Figure occurs to as a result of proinflammatory of the endothelium inflammatory and cells to from the blood into to endothelial cell dysfunction, inflammation, and formation of the endothelium also in alterations in the function of endothelial cells lead to alterations in vasomotor the endothelium such as and that a of in is caused by increased of a that can lead to abnormal As sepsis alterations in can result in and impaired microcirculatory blood severe sepsis, of endothelial can lead to endothelial dysfunction (Figure dysfunction is a common in sepsis. The dysfunction may be due to the of proinflammatory cytokines on endothelial cells or to endothelial produced by the or For example, patients with severe sepsis have endothelial cell dysfunction with decreased of and protein C on endothelial cells and a in the levels of results of endothelial cell dysfunction in sepsis are impaired and of coagulation that to endothelial cell and activation of sepsis alterations in organ function may The of patients with severe sepsis is related to the and of organ inflammation and occurring of the coagulation system lead to the of microvascular in a that may contribute to the of multiple organ dysfunction organ dysfunction syndrome is as a major cause of mortality in patients with A variety of potential pathophysiological mechanisms have been to result in the These include perfusion, and endothelial cell number of have been to and the of organ dysfunction in were to be used in to and are used in clinical of to treat sepsis. With most of these of disease clinical criteria and laboratory markers to assess the and central nervous (Table Although the of sepsis in terms of the organ involved be the are the most common site of are the and the due to sepsis is related to the number of organ Patients with severe sepsis have a of 2 or This number is associated with a mortality of 30% to With the of each a risk of death by a of to early and of multiple organ dysfunction syndrome are key in increased mortality rates in patients with C is a anticoagulation and is involved in the formation of thrombin in the and in microvascular C in an Activation of protein C of the protein to 2 endothelial cell-surface and endothelial protein C protein C is a of a group of that include tissue factor pathway inhibitor and antithrombin protein C has and and can pathophysiological associated with severe activated protein C release from and subsequent to the coagulation by factors and of the coagulation cascade to generation of thrombin, and stimulates fibrinolysis by reducing the of inhibitors of protein C can plasminogen activator the of tissue plasminogen activator and Additionally, by limiting the formation of thrombin, activated protein C fibrinolytic by the activation of thrombin activatable fibrinolysis of the protein C system play an important role in patients with severe sepsis. of protein C decrease the of clinical manifestations of severe sepsis and septic concentrations of protein C in patients with sepsis are associated with a clinical including higher prevalence of shock, in the intensive care and without of infectious of shock, disseminated intravascular coagulation, or of protein C mortality and the coagulopathy associated with the of of However, in order to the of this the be In severe sepsis, of by endothelial cells is Consequently, activation of protein C is and patients from its protective In activated protein C the concentrations of markers of inflammation and sepsis-associated coagulopathy in patients with severe assessment and monitoring of patients who are at risk for sepsis and astute observation of the of in patients with severe sepsis are key components of nursing care. As of critical care nurses can the of patients. nursing and infection control nurses can the of sepsis and promote early recognition of acute organ system number of nursing care can be used to and treat patients with severe sepsis (Table These include monitoring the vital and and other important laboratory and to promote early diagnosis of sepsis.The of a nursing assessment of a with sepsis is of and organ the findings that may indicate the of a systemic inflammatory response to infection is a in vital signs, an in body is of the systemic inflammatory response and is due to release of mediators and endothelial is a blood less than or a reduction of than from in the of other of occurs when is to and therapy with and Recent that may be more than or as a in septic shock, blood urine and with or without may also and a state may be by elevated and systemic assessment of and use of therapy to and to systemic can in patients with severe sepsis and septic Although the of use in sepsis remains in a therapy the risk of death in patients with septic and and alterations in are other key of patients with sepsis and adult respiratory syndrome in to of in can also occur in severe sepsis, because of and dysfunction is by decreased urine output, to a state of increased levels of and increased concentrations of Although increasing blood flow to has been no evidence or therapy may be the use of or continues to be organ that may in patients with severe sepsis include dysfunction with coagulopathy and such as and Recent on the of and in patients that intensive therapy to blood levels at or less than and Although changes in including confusion, and are common in patients with severe sepsis, the of these changes is not often as an indication of central nervous system dysfunction associated with severe severe sepsis is key of nursing care are related to providing and are important in the of is also an of care. on the of critical of information as an important of care. patients and their is also to that they and provided in severe of sepsis may be the most important for remains the most to the incidence of infection, the of in hospitalized can be by a or and with universal to infection control and to can also sepsis. such as and care of are important in the risk for infection in on the of the use of care of and to the risk of infection. Other of nursing care such as for because of or in monitoring the of and and astute clinical assessment to patients at risk for sepsis can contribute to the early and of infection to the risk for care nurses are the most closely involved in the care of patients and have the to patients at risk for and to for signs and symptoms of severe In addition, critical care nurses are also the who patients with severe sepsis to assess the of and to to of an is as the for the intensive care and the of care has been As key of critical care nurses play an important role in the and of sepsis and can in patients with severe alfa (activated) is activated protein it has the as activated protein C from and evidence that it has and The of drotrecogin alfa (activated) was recently in a In the C Evaluation in Severe Sepsis the of drotrecogin alfa (activated) was in patients with severe sepsis. for entry into the study or infection, at 3 indications of and evidence of at organ system dysfunction, as defined by of no than were to 2 and a of drotrecogin alfa (activated), per or Patients were from they were at high risk for criteria active 3 2 or severe associated with an increased risk of of an or and evidence of Patients were also they a less than were in a state and not expected to a of or failure, acute pancreatitis, or therapy 3 or were receiving at higher than for or at a of more than outcome was mortality due to all at the of In at the of the the trial was by the independent and monitoring because it met a criteria for with drotrecogin alfa (activated) produced a reduction in mortality and a reduction in the risk of mortality due to all in patients with severe sepsis rates were in the group with drotrecogin alfa (activated) and in the group a The number of patients at high risk for death was in mortality in patients with normal protein C concentrations and in with protein C levels were and levels were in patients with drotrecogin alfa activated than in patients with the in drotrecogin alfa (activated) were in of patients to or infectious with the and of drotrecogin alfa (activated), the of patients who a as a was higher for the than for the rates for patients with drotrecogin alfa (activated) and were and events often were due to to a blood or or to of a such as the or In the drotrecogin alfa (activated) a events associated with drotrecogin alfa (activated) were to and most of the events were the of the results of the study and of the Food and Drug Administration approved drotrecogin alfa (activated), or Xigris, for the of severe sepsis in adult patients with a high risk of mortality (eg, as determined by scores on Acute Physiology and Chronic Health Evaluation II). As a new for sepsis, drotrecogin alfa (activated) can mortality in patients with severe sepsis and organ of critical care nurses will be directly involved with the administration of drotrecogin alfa (activated), knowledge related to and of the is is a list of nursing care related to the of drotrecogin alfa alfa (activated) should be at the rate of per of body per for a of on drotrecogin alfa (activated) may be to the critical care In nurses are directly involved in the it is drotrecogin alfa (activated) has patients with this should be for clinical evidence of the should be important the of drotrecogin alfa (activated) should be Continued use of other that the coagulation system should be has been continued use of drotrecogin alfa (activated) may be and of drotrecogin alfa (activated) are and of the is 2 the is Consequently, drotrecogin alfa (activated) should be 2 an or with an risk of has been of drotrecogin alfa (activated) can be an and a or for is of levels of protein C is not in patients with drotrecogin alfa The an in patients with both normal and levels of protein the levels of protein C may not with the because patients with severe sepsis may have endothelial cell dysfunction and be to protein C into its active no for activated protein C are of the activated is not a to assess the of drotrecogin alfa In addition, of the activated may be due to factors independent of the Although can be used in with the clinical of patients to assess the coagulopathy associated with sepsis, most are not to the that drotrecogin alfa (activated) has on the with acute organ dysfunction is a common and often It is associated with inflammatory, prothrombotic, and impaired fibrinolytic In with anti-inflammatory in patients with sepsis, mortality due to all was not the trial of drotrecogin alfa (activated), a protein with and resulted in the first successful outcome in reducing mortality rates in patients with severe sepsis. However, the mechanisms by which drotrecogin alfa (activated) its are not The of drotrecogin alfa (activated) is a new therapy in the of severe sepsis. This is the first of a new of and the only to mortality in sepsis. of critical care nurses for patients with severe sepsis, should the pathophysiological for this and the issues related to administration of drotrecogin alfa (activated) and monitoring of patients with this is a of the of