Advances in Treating Patients With Severe Sepsis
2003; American Association of Critical-Care Nurses; Volume: 23; Issue: 3 Linguagem: Inglês
10.4037/ccn2003.23.3.16
ISSN1940-8250
Autores Tópico(s)Intensive Care Unit Cognitive Disorders
ResumoA 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, significantly larger than the skin.21 The endothelium is a dynamic organ that is differentially regulated by a variety of signals over space and time.Physiologically, normal endothelium has an anticoagulant phenotype. In sepsis, injury to the endothelium occurs when proinflammatory mediators are released from monocytes and macrophages responding to infection (Figure 2). Although the release of mediators promotes recruitment of neutrophils and accumulation of platelets to wall off a site of infection, continued release of cytokines can result in endothelial damage. After injury, endothelial cells may downregulate the synthesis and expression of antithrombotic molecules such as thrombomodulin, endothelial cell receptors for protein C, and tissue factor pathway inhibitor.Normally, the endothelium expresses only low levels of adhesion molecules such as selectins.20 Upregulation of these adhesion molecules can promote interactions between the endothelium, white blood cells, and platelets. This interaction can promote accumulation of leukocytes at the site of injury and promote accumulation of platelet thrombi (Figure 3). Increased vascular permeability occurs 6 to 24 hours as a result of proinflammatory cytokine triggering.23 Physical disruption of the endothelium then allows inflammatory fluid and cells to move from the blood into interstitial spaces, further adding to endothelial cell dysfunction, inflammation, and formation of edema.23Because the endothelium also functions in vasoregulation, alterations in the function of endothelial cells lead to alterations in vasomotor tone. Normally, the endothelium secretes substances such as nitric oxide and prostacyclin that produce a steady level of vasodilation. Impairment in vasoregulation is caused by increased production of nitric oxide, a condition that can lead to abnormal endothelium-dependent vascular relaxation.23 As sepsis progresses, alterations in vasoregulation can result in vasodilatation, unrefractory hypotension, and impaired microcirculatory blood flow.In severe sepsis, progression of endothelial damage can lead to endothelial dysfunction (Figure 4). Endothelial dysfunction is a common element in sepsis. The dysfunction may be due to the effects of proinflammatory cytokines on endothelial cells or to direct endothelial injury produced by the infecting organism or endotoxin. For example, patients with severe meningococcal sepsis have endothelial cell dysfunction with decreased expression of thrombomodulin and protein C receptors on endothelial cells and a marked elevation in the plasma levels of thrombomodulin.24The results of endothelial cell dysfunction in sepsis are impaired endothelium-derived vascular relaxation, altered endothelium-derived antiadhesive properties, and altered endothelium-derived modulation of coagulation that contributes to endothelial cell injury and further activation of coagulation.23As sepsis progresses, alterations in organ function may occur. The prognosis of patients with severe sepsis is related to the severity and duration of organ dysfunction.25–27 Systemic inflammation and simultaneously occurring derangement of the coagulation system lead to the deposition of microvascular thrombi in various organs, a condition that may contribute to the pathogenesis of multiple organ dysfunction syndrome.28Multiple organ dysfunction syndrome is currently recognized as a major cause of mortality in patients with sepsis.29 A variety of potential pathophysiological mechanisms have been postulated to result in the syndrome. These include inadequate tissue/organ perfusion, cellular injury, ischemia, and diffuse endothelial cell injury.29A number of scoring systems have been developed to objectively describe and measure the level of organ dysfunction in critically ill patients.29 Most scoring systems were designed to be used in serial assessments to describe evolving morbidity and are used primarily in clinical evaluation of interventions to treat sepsis. With most of these tools, evaluation of disease severity involves using clinical criteria and laboratory markers to assess the respiratory, renal, hepatic, gastrointestinal, hematologic, cardiovascular, and central nervous systems (Table 4). Although the progression of sepsis in terms of the organ systems involved cannot be predicted, the lungs are the most common site of infection; next are the abdomen and the urinary tract.6,30 Mortality due to sepsis is related to the number of dysfunctional organ systems. Patients with severe sepsis have a median of 2 failed or dysfunctional organs.6 This number is associated with a mortality of 30% to 40%. With the failure of each additional organ, a patient's risk of death increases by a mean of 15% to 20%.6 Therefore, early detection and treatment of multiple organ dysfunction syndrome are key in preventing increased mortality rates in patients with sepsis.Protein C is a vitamin K–dependent anticoagulation protease and is involved in regulating the formation of thrombin in the microvasculature and in preventing microvascular thrombosis. Protein C circulates in an inactive state. Activation of protein C requires binding of the protein to 2 endothelial cell-surface receptors: thrombomodulin and endothelial protein C receptor.24,31 Activated protein C is a member of a group of natural anticoagulants that include tissue factor pathway inhibitor and antithrombin III.Activated protein C has antithrombotic, anti-inflammatory, and profibrinolytic properties and potentially can correct pathophysiological abnormalities associated with severe sepsis.32,33 Specifically, activated protein C inhibits cytokine release from monocytes, reduces neutrophil rolling and subsequent adhesion to the endothelium, inhibits coagulation by inactivating factors VIIIa and Va of the coagulation cascade to prevent generation of thrombin, and stimulates fibrinolysis by reducing the concentration of inhibitors of fibrinolysis.30,31,34,35 Activated protein C can inhibit plasminogen activator inhibitor-1, thus preventing the blockade of endogenous tissue plasminogen activator and facilitating fibrinolysis.36 Additionally, by limiting the formation of thrombin, activated protein C indirectly enhances endogenous fibrinolytic activity by preventing the activation of thrombin activatable fibrinolysis inhibitor.36Abnormalities of the protein C system play an important role in patients with severe sepsis. Concentrations of protein C decrease before the onset of clinical manifestations of severe sepsis and septic shock.37 Low concentrations of protein C in patients with sepsis are associated with a poor clinical outcome, including lower survival rate, higher prevalence of shock, longer stays in the intensive care unit, and fewer days without mechanical ventilation, regardless of age, infectious causes, presence of shock, disseminated intravascular coagulation, or hyper-coagulation.15 Experimentally, infusions of protein C prevented mortality and reversed the coagulopathy associated with the infusion of lethal doses of Escherichia coli.38,39 However, in order to obtain the benefits of this protein, the molecule must be activated. In severe sepsis, expression of thrombomodulin by endothelial cells is decreased. Consequently, activation of protein C is impaired, and patients cannot benefit from its protective properties. In recent studies,30,40 recombinant human activated protein C reduced the concentrations of markers of inflammation and sepsis-associated coagulopathy in patients with severe sepsis.Comprehensive assessment and monitoring of patients who are at risk for sepsis and astute observation of the effects of treatment in patients with severe sepsis are key components of nursing care. As members of critical care teams, nurses can influence the outcomes of acutely ill patients. Through proper nursing and infection control techniques, nurses can prevent the development of sepsis and promote early recognition of acute organ system dysfunction.A number of nursing care measures can be used to assess, monitor, and treat patients with severe sepsis (Table 5). These measures include monitoring the vital signs; hemodynamic, ventilatory, renal, hematologic, hepatic, neurological, and nutritional status; and other important laboratory and physical parameters to promote early diagnosis of sepsis.The initial focus of a nursing assessment of a patient with suspected sepsis is evaluation of hemodynamic stability and organ perfusion.41 Among the initial findings that may indicate the presence of a systemic inflammatory response to infection is a change in vital signs, especially an elevation in body temperature.3 Hypotension is another hallmark of the systemic inflammatory response and is due to release of mediators and altered endothelial vasoregulation. By definition, hypotension is a systolic blood pressure less than 90 mm Hg or a reduction of greater than 40 mm Hg from baseline in the absence of other causes of hypotension.7 Septic shock occurs when hypotension is refractory to fluid resuscitation, and emergent stabilization requires aggressive therapy with vasopressors and inotropes.42 Recent data43 suggest that norepinephrine may be more advantageous than high-dose dopamine or epinephrine as a vasopressive agent in septic shock, improving arterial blood pressure, urine flow, and oxygen delivery.Tachycardia with or without ectopy may also occur, and a hyper-dynamic cardiovascular state may be manifested by elevated cardiac output and low systemic vascular resistance. Early assessment of hemodynamic status and use of goal-directed therapy to optimize cardiac preload, afterload, and contractility to maximize systemic oxygen delivery can improve outcomes in patients with severe sepsis and septic shock.44 Although the benefit of steroid use in sepsis remains controversial, in a recent study,45 low-dose corticosteroid therapy reduced the risk of death in patients with septic shock and relative adrenal insufficiency.Tachypnea and alterations in oxygenation are other key findings; nearly 85% of patients with sepsis require mechanical ventilation, and adult respiratory distress syndrome develops in up to 40% of patients.3,6 Alterations in renal functioning can also occur in severe sepsis, because of hypotension and hypoperfusion. Renal dysfunction is reflected by decreased urine output, eventually to a state of oliguria; increased levels of serum urea nitrogen; and increased concentrations of creatinine.43 Although increasing renal blood flow to improve renal functioning has traditionally been advocated, no definitive evidence supports specific diuretic or vasodilatory therapy. Renal replacement therapy may be indicated; however, the preferential use of continuous renal replacement or intermittent hemodialysis continues to be debated.46Other organ dysfunctions that may develop in patients with severe sepsis include hematologic dysfunction with coagulopathy and metabolic abnormalities such as altered glucose metabolism and lactic acidosis.3 Recent data47 on the treatment of hyperglycemia and insulin resistance in critically ill patients suggest that intensive insulin therapy to maintain blood glucose levels at or less than 6.1 mmol/L (110 mg/dL) reduces morbidity and mortality. Although changes in mental status, including restlessness, confusion, and obtundation are common in patients with severe sepsis, the presence of these changes is not often recognized as an indication of central nervous system dysfunction associated with severe sepsis.Once severe sepsis is confirmed, key aspects of nursing care are related to providing comprehensive treatment. Pain relief and sedation are important in promoting patients' comfort. Meeting the needs of patients' families is also an essential component of care. Research48,49 on the needs of patients' families during critical illness supports provision of information as an important aspect of family care. Teaching patients and their families is also essential to ensure that they understand various treatments and interventions provided in severe sepsis.Ultimately, prevention of sepsis may be the single most important measure for control.50 Handwashing remains the most effective way to reduce the incidence of infection, especially the transmission of nosocomial infections in hospitalized patients.51 Good hand hygiene can be achieved by using either a waterless, alcohol-based product or antibacterial soap and water with adequate rinsing.52,53 Using universal precautions, adhering to infection control practices, and instituting measures to prevent nosocomial infections can also help prevent sepsis. Nursing measures such as oral care, proper positioning, turning, and care of invasive catheters are important in decreasing the risk for infection in critically ill patients.54,55 Newly released guidelines56 on the prevention of catheter-related infections stress the use of surveillance, cutaneous antisepsis during care of catheter sites, and catheter-site dressing regimens to minimize the risk of infection. Other aspects of nursing care such as sending specimens for culture because of suspicious drainage or elevations in temperature, monitoring the characteristics of wounds and drainage material, and using astute clinical assessment to recognize patients at risk for sepsis can contribute to the early detection and treatment of infection to minimize the risk for sepsis.Critical care nurses are the healthcare providers most closely involved in the daily care of critically ill patients and so have the opportunity to identify patients at risk for and to look for signs and symptoms of severe sepsis.57,58 In addition, critical care nurses are also the ones who continually monitor patients with severe sepsis to assess the effects of treatment and to detect adverse reactions to various therapeutic interventions. Use of an intensivist-led multidisciplinary team is designated as the best-practice model for the intensive care unit, and the value of team-led care has been shown.59,60 As key members of intensivist-led multidisciplinary teams, critical care nurses play an important role in the detection, monitoring, and treatment of sepsis and can affect outcomes in patients with severe sepsis.Drotrecogin alfa (activated) is recombinant human activated protein C; it has the same amino acid sequence as activated protein C derived from human plasma. Clinical and experimental evidence indicates that it has antithrombotic, anti-inflammatory, and profibrinolytic properties. The efficacy of drotrecogin alfa (activated) was recently studied in a large international, multi-center, randomized, double-blind, placebo-controlled trial. In the Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial,30 the effectiveness of drotrecogin alfa (activated) was examined in 1690 patients with severe sepsis. Criteria for entry into the study included known or suspected infection, having at least 3 indications of SIRS, and evidence of at least 1 organ system dysfunction, as defined by PROWESS criteria, of no longer than 24 hours' duration.Patients were randomized to 2 groups and received a 96-hour infusion of drotrecogin alfa (activated), 24 μg/kg per hour, or placebo. Patients were excluded from participation if they were at high risk for bleeding. Specific exclusion criteria included active internal bleeding, recent (within 3 months) hemorrhagic stroke, recent (within 2 months) intracranial or intraspinal surgery, severe head trauma, trauma associated with an increased risk of life-threatening bleeding, presence of an epidural catheter, intracranial neoplasm or mass lesion, and evidence of cerebral herniation.30 Patients were also excluded if they had a platelet count less than 30000/μL (30 ×109/L), were in a moribund state and not expected to survive, had a history of transplantation, had known or suspected liver failure, had acute pancreatitis, or had received thrombolytic therapy within 3 days or were receiving warfarin, low molecular weight heparin at higher doses than recommended for prophylactic use, or acetylsalicylic acid at a dose of more than 650 mg/day.30The primary outcome parameter was mortality due to all causes at 28 days after the start of drug administration. In June 2000, at the time of the second interim analysis, the PROWESS trial was stopped by the independent data safety and monitoring board because it met a priori stopping criteria for efficacy.30Treatment with drotrecogin alfa (activated) produced a 6.1% absolute reduction in mortality and a 19.4% reduction in the relative risk of mortality due to all causes in patients with severe sepsis (P=.005). Mortality rates were 24.7% in the group treated with drotrecogin alfa (activated) and 30.8% in the group given a placebo (P=.005).28 The number of lives saved among patients at high risk for death was increased. Treatment-associated reductions in mortality occurred in patients with normal protein C concentrations and in those with low protein C concentrations. Plasma D-dimer levels were significantly lower and serum IL-6 levels were significantly greater in patients treated with drotrecogin alfa activated than in patients treated with the placebo. No substantial differences in drotrecogin alfa (activated) treatment were observed in subgroupings of patients according to sex, ethnic origin, or infectious agent.Consistent with the antithrombotic and profibrinolytic effects of drotrecogin alfa (activated), the percentage of patients who had a bleeding event reported as a serious adverse event was higher (3.5%) for those given the drug than for those given the placebo (2%; P=.06).30 During infusion periods, bleeding rates for patients treated with drotrecogin alfa (activated) and placebo were 2.4% and 1%, respectively (P=.06). Serious bleeding events often were due to injury to a blood vessel (traumatic or iatrogenic) or to instrumentation of a highly vascular organ, such as the kidney or lung. In the PROWESS trial, drotrecogin alfa (activated) had a favorable risk-benefit profile. Adverse events associated with drotrecogin alfa (activated) treatment were limited to bleeding, and most of the events were manageable.On the basis of the results of the PROWESS study and of previous studies, the Food and Drug Administration approved drotrecogin alfa (activated), or Xigris, for the treatment 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 treatment option for sepsis, drotrecogin alfa (activated) can reduce mortality in patients with severe sepsis and organ failure within 48 hours of diagnosis.Because critical care nurses will be directly involved with the administration of drotrecogin alfa (activated), knowledge related to preparation and infusion of the drug is essential. Table 6 is a list of nursing care related to the infusion of drotrecogin alfa (activated).Drotrecogin alfa (activated) should be administered intravenously at the recommended infusion rate of 24 μg per kilogram of actual body weight per hour for a total duration of 96 hours. Depending on institutional pharmacy policies, drotrecogin alfa (activated) may be reconstituted before delivery to the critical care area. In some institutions, nurses are directly involved in reconstituting the drug before it is administered.Because drotrecogin alfa (activated) has antithrombotic properties, patients treated with this agent should be monitored for clinical evidence of bleeding. If bleeding occurs, the patient's physician should be notified. If clinically important bleeding occurs, the infusion of drotrecogin alfa (activated) should be stopped immediately. Continued use of other agents that affect the coagulation system should be carefully assessed. Once adequate hemostasis has been achieved, continued use of drotrecogin alfa (activated) may be reconsidered.61The half-life-α and half-life-β of drotrecogin alfa (activated) are 13 minutes and 1.6 hours, respectively. Therefore, 90% of the drug is eliminated within 2 hours after the infusion is stopped. Consequently, drotrecogin alfa (activated) should be discontinued 2 hours before an invasive surgical procedure or procedures with an inherent risk of bleeding. Once adequate hemostasis has been achieved, infusion of drotrecogin alfa (activated) can be restarted 1 hour after an uncomplicated, minor procedure and 12 hours after a major, invasive procedure or surgery.61 Monitoring for bleeding complications is essential.Assessment of plasma levels of protein C is not necessary in patients treated with drotrecogin alfa (activated). The drug exerts an effect in patients with both normal and low levels of protein C. Furthermore, the levels of protein C may not correlate with the drug's effects because patients with severe sepsis may have endothelial cell dysfunction and be unable to convert protein C into its active form. Last, no simple, readily available assay systems for activated protein C are currently available.61Measurement of the activated partial thromboplastin time is not a reliable means to assess the pharmacodynamic effect of drotrecogin alfa (activated). In addition, prolongation of the activated partial thromboplastin time may be due to factors independent of the drug's effects. Although prothrombin times can be used in conjunction with the clinical condition of patients to assess the coagulopathy associated with sepsis, most instruments are not precise enough to detect the small effect that drotrecogin alfa (activated) has on the prothrombin time.Sepsis with acute organ dysfunction is a common and often fatal disorder. It is associated with significant inflammatory, prothrombotic, and impaired fibrinolytic components. In numerous trials with anti-inflammatory agents in patients with sepsis, 28-day mortality due to all causes was not significantly reduced. Recently, the PROWESS trial of drotrecogin alfa (activated), a recombinant human protein with anti-inflammatory, antithrombotic, and profibrinolytic properties, resulted in the first successful outcome in reducing mortality rates in patients with severe sepsis. However, the specific mechanisms by which drotrecogin alfa (activated) exerts its effect are not completely understood. The development of drotrecogin alfa (activated) is a promising new therapy in the treatment of severe sepsis. This drug is the first member of a new class of compounds and the only modulator shown to reduce mortality in sepsis. Members of critical care teams, especially nurses caring for patients with severe sepsis, should understand the pathophysiological basis for this intervention and the practical issues related to administration of drotrecogin alfa (activated) and monitoring of patients treated with this drug.Dr Kleinpell is a member of the National Speakers Bureau of Eli Lilly & Co.
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