HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) Respond to This Article Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Take the CE Test Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ely, E. W. Articles by Goyette, R. E. Search for Related Content PubMed PubMed Citation Articles by Ely, E. W. Articles by Goyette, R. E.

CE Article

Advances in the Understanding of Clinical Manifestations and Therapy of Severe Sepsis: An Update for Critical Care Nurses

	Abstract

Top Abstract Systemic Inflammatory Response... Multiple Organ Dysfunction... Hemostatic Abnormalities in... Clinical Evaluation of Patients... Pharmacological Treatment of... Lessons Learned From the... Practical Bedside Application of... The Role of Critical... Conclusions References

 
Severe sepsis is a major public health concern and a burden on the healthcare system. Despite improvements in efforts to control the source of infection and increased recognition by healthcare providers of patients with the disease, the mortality rate remains unacceptably high, from 30% to 50%. The systemic inflammatory response syndrome criteria are used as diagnostic indicators of sepsis when they occur in patients with known or suspected infection. The outcome of a patient with severe sepsis is often related to the occurrence of sepsis-induced multiple organ dysfunction syndrome. Multiple organ dysfunction syndrome appears to result from a cascade of organism-related factors, inflammatory mediators, endothelial injury, disturbed hemostasis, and microcirculatory abnormalities. In patients with severe sepsis, derangements of inflammation and coagulation are tightly linked. Although numerous clinical trials focused on interventions in one or the other of the inflammatory and coagulation systems failed to show reduced mortality due to sepsis, a member of a new class of drugs called "cogins" was effective. In its active form, protein C has anti-inflammatory, antithrombotic, and profibrinolytic properties that can reduce organ injury associated with severe sepsis. A recombinant form of activated protein C, drotrecogin alfa (activated), significantly reduces 28-day mortality due to all causes in patients with severe sepsis and has an acceptable safety profile. This review provides an overview of severe sepsis, highlighting recent advances in treatment of the disease and the role of critical care nurses.

Notice to CE enrollees: A closed-book, multiple-choice examination following this article tests your understanding of the following objectives: Recognize definitions and terminology used to describe sepsis and its sequelae Identify factors related to the development of multiple organ dysfunction syndrome (MODS) Describe the role of recombinant human activated protein C in the treatment of severe sepsis

Central elements in the management of patients with severe sepsis include the use of diligent efforts to control the source of infection and appropriate antibiotics, with supportive care provided in the intensive care unit, including fluid resuscitation, vasopressors, ventilatory support, and renal replacement therapy.⁶ Despite improvements in these interventions and greater sophistication in diagnosis and monitoring strategies, the mortality rate associated with severe sepsis remains unacceptably high and has changed little in recent decades.^1,2,7,8 Interventions that might reduce deaths due to this disease are urgently needed.

Numerous clinical trials have enrolled thousands of patients in an attempt to find a specific agent to modulate the underlying disease process in sepsis. Candidate antisepsis therapies have included agents that target host cell activation, mediators of the inflammatory response, agents that boost the immune response, and prostaglandin inhibitors. Until recently, however, no modulator therapy has reduced 28-day mortality due to all causes in patients with severe sepsis.^1,9 The recent Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study was the first clinical trial to show a clinically significant, successful intervention in the course of severe sepsis.¹⁰

In this article, we focus on the systemic inflammatory response syndrome (SIRS) and coagulation and fibrinolytic changes at the level of the microvasculature endothelium that may be central to the development of the multiple organ dysfunction syndrome (MODS) in patients with severe sepsis. Results of the PROWESS trial, which indicated that treatment with recombinant human activated protein C, drotrecogin alfa (activated), can significantly reduce mortality in patients with severe sepsis, are reviewed. Implications for critical care nurses, who are integral members of the critical care team, are also discussed.

	Systemic Inflammatory Response Syndrome

Top Abstract Systemic Inflammatory Response... Multiple Organ Dysfunction... Hemostatic Abnormalities in... Clinical Evaluation of Patients... Pharmacological Treatment of... Lessons Learned From the... Practical Bedside Application of... The Role of Critical... Conclusions References

 
Before 1992, systemic clinical manifestations of a response to infection were broadly termed "sepsis." These manifestations are well known to clinicians and include alterations in temperature, heart rate, respiratory rate, and white blood cell count and composition. However, similar changes can occur in patients with a variety of noninfectious diseases or conditions, including severe burns, acute necrotizing pancreatitis, severe trauma, and hemorrhagic shock.⁸ Therefore, the presence of these alterations alone is not prima facie evidence for a septic response.

In a 1992 consensus conference, representatives from the American College of Chest Physicians (ACCP) and the Society of Critical Care Medicine (SCCM) met to clarify definitions and terminology associated with sepsis and its sequelae⁸ (Table 1). Recognizing that the diverse signs and symptoms of patients with sepsis represent a continuum of the host’s response to injury, the committee developed standard definitions for sepsis, severe sepsis, septic shock, and the multiple organ dysfunction syndrome. Conferees also proposed a new term for the systemic manifestations of an inflammatory reaction: the systemic inflammatory response syndrome. This hierarchical construct of definitions was intended to provide a basis for consistent application of diagnosis and treatment, and recent evidence indicates that it largely succeeded in doing so.¹¹

Although the focus of the ACCP/SCCM definitions is inflammatory changes associated with sepsis, without recognition of the importance of the tight link between the hemostatic system and inflammation, the committee acknowledged that the definitions are limited and will evolve with further study.⁸ Since publication of these definitions in 1992, growing concerns about the nonspecificity of certain SIRS criteria, together with advances in our understanding of the pathophysiology of severe sepsis and MODS, have prompted a reevaluation of the definitions. In December 2001, a second conference was organized by the ACCP, SCCM, the American Thoracic Society, and the European Society of Intensive Care Medicine to update the original definitions. As a result, an expanded list of signs and symptoms was outlined to facilitate recognition of sepsis.¹⁴ These include chills, decreased urine output, decreased skin perfusion, poor capillary refill, skin mottling, decreased platelet count, petechiae, hypoglycemia, and unexplained change in mental status.¹⁴

	Multiple Organ Dysfunction Syndrome

Top Abstract Systemic Inflammatory Response... Multiple Organ Dysfunction... Hemostatic Abnormalities in... Clinical Evaluation of Patients... Pharmacological Treatment of... Lessons Learned From the... Practical Bedside Application of... The Role of Critical... Conclusions References

 
The issue of MODS was brought to the attention of the medical community when formally addressed by the ACCP/SCCM conferees in 1991⁸ (Table 1). The committee defined MODS as an entity that produced progressive physiological failure of several organ systems in acutely ill patients such that homeostasis could not be maintained without intervention.

Several studies^15–17 indicated that mortality in severe sepsis is a function of the number of failing organ systems and the severity of dysfunction within the system. In fact, MODS is now regarded as the most common cause of death among patients in noncoronary critical care units.¹⁸

The prognosis of patients with severe sepsis is related to the severity of organ dysfunction at the time of admission to the intensive care unit¹⁵ (Figure 1). Scoring systems such as the Sequential Organ Failure Assessment (SOFA) are useful tools for assessing and quantifying organ dysfunction and failure over time. In the SOFA system, organ system dysfunctions are used to evaluate morbidity in critically ill patients¹⁹ (Table 2). Additionally, the SOFA score is a good indicator of mortality. Ferreira et al¹⁹ found that patients with the highest SOFA score during the first 48 hours of care in the intensive care unit had a predicted mortality rate of 95% (Figure 2).

View larger version (11K): [in this window] [in a new window]   Figure 1 The number of dysfunctional organs upon admission to the intensive care unit, as defined by the Sequential Organ Failure Assessment (SOFA) score, is strongly related to the probability of survival in the unit. The mortality rate was lowest in patients with no dysfunctional organs, and increased progressively with dysfunction of 1, 2, 3, and 4 or more (83%) organs (2=229; P<.00001).

View larger version (16K): [in this window] [in a new window]   Figure 2 Initial score on the Sequential Organ Failure Assessment (SOFA) vs mortality rate. During the first 48 hours after admission to the intensive care unit, a high initial score is associated with an increased risk of mortality (a score >11 is predictive of a mortality rate of 95%).

  Primary Cellular Injury.   Primary cellular injury may be due to underlying disease processes (eg, severe tissue injury or a nidus of infection) or to toxic effects of various mediators.^18,20,26 Endothelial damage can increase vascular permeability and shunt flow.²⁷ With these and other sepsis-induced changes, maldistribution of blood flow can impair delivery of oxygen, nutrients, and other substrates essential to organ preservation. Severe sepsis is commonly accompanied by decreased cardiac output, and alterations in the perfusion of a specific organ system may occur.^28,29

  Microaggregates.   Microaggregates of platelets, neutrophils, red blood cells, and fibrin can impair micro-circulatory blood flow, producing tissue ischemia that may persist despite reperfusion.^18,30 Perhaps because of enhanced stagnation and microcirculatory thrombosis, sepsis may be accompanied by loss of deformability of red blood cells, an important property for passage through vessels with a smaller diameter.³¹ On reperfusion of ischemic tissues, release of toxic oxygen metabolites can induce apoptosis through changes related to oxidative stress, thus compounding previous endothelial injury and dysfunction.²⁰

  Endothelial Cell Injury.   Various sepsis-related factors, including excessive stimulation by proinflammatory cytokines or other systemic mediators, can cause endothelial cell damage and dysfunction. Activation of endothelial cells involves increased expression of potentially injurious molecules, including the inducible form of nitric oxide synthase, which generates excess nitric oxide, and intercellular adhesion molecules, which promote neutrophil chemotaxis and endothelial cell interactions.²⁷ Vasomotor tone may be directly altered by local mediators, some of which (eg, endothelin, vasopressin) act as vasoconstrictors. Other mediators (eg, nitric oxide, bradykinin, histamine) produce vasodilatation, leading to low perfusion pressures or hypotension. Diffuse endothelial cell reperfusion injury can lead to edema related to capillary leakage, cellular infiltration, and continued tissue damage. Although often first observed as pulmonary edema, these changes also occur in the liver, kidney, heart, skin, muscle, and brain of patients with severe sepsis.

  Metabolic Derangement.   Even if blood flow is adequate, the ability of cells to extract or use oxygen and substrates may be impaired by mitochondrial dysfunction or other metabolic disturbances in sepsis.^18,20 Endo-toxin has complex effects on cellular metabolism and can reduce maximal oxygen consumption independent of hypoxic injury.³² Oxidants produced during endotoxin-induced shock can trigger activation of the nuclear enzyme poly (adenosine diphosphate–ribose) synthetase, leading to intracellular energetic failure and, at least experimentally, mediating pulmonary microvascular and intestinal mucosal dysfunction.³³ Sepsis induces a hypermetabolic state characterized by an increase in resting energy consumption, extensive protein and fat catabolism, negative nitrogen balance, hyperglycemia, and an increase in hepatic gluconeogenesis. Together, these metabolic disturbances suggest a mechanism for alterations in the function of the gut as a barrier, which may permit translocation of bacteria, bacterial products, and other mediators into the portal or systemic circulation or the mesenteric lymph.³⁴

  Humoral Mediators.   Humoral mediators play a myriad of roles in systemic host responses that characterize severe sepsis and MODS. When stimulated by bacterial pathogens or their products, monocytes or macrophages secrete TNF-and IL-1, which can act directly or indirectly through secondary mediators such as IL-6, IL-8, and platelet-activating factor.^6,28,35 These responses play a critical role in host defenses by attracting leukocytes to the site of infection. However, as excess levels of circulating cytokines induce a generalized inflammatory response, concomitant activation of the endothelium and circulating immune effector cells promotes neutrophil chemotaxis and endothelial cell interactions. These interactions, plus activation of complement and direct effects of thrombin and circulating cytokines, may directly injure the endothelium or cause the release of lysosomal enzymes and other substances that can then induce microvascular injury.^35,36 Anti-inflammatory processes are activated to counterbalance the systemic inflammatory response and are characterized by increased levels of circulating anti-inflammatory cytokines (eg, IL-4, IL-13), enhanced expression of receptor antagonists, and shedding of soluble receptors.^20,35,37,38 This paradoxical coexistence of proinflammatory and anti-inflammatory substances and their conflicting signals may also induce a state of immune dysregulation, characterized by decreased ability of monocytes to process antigens, impaired function of polymorphonuclear neutrophilic leukocytes, and eventual apoptosis.

  Therapy-Induced Dysfunction.   Various treatments initiated by healthcare providers may contribute to organ dysfunction. For example, mechanical ventilation at higher tidal volumes (eg, 10–12 mL/kg) and blood transfusions have been associated with major infections and are independent risk factors for development of MODS and death.^39–45 Other commonly implicated treatments include administration of nephrotoxic antimicrobial agents and use of invasive devices. Hemo-dialysis may promote systemic anticoagulation or activation of polymorphonuclear neutrophilic leukocytes, leading to damage to the microvasculature in the lungs or other organs.

Hyperglycemia is common in critically ill patients; many have blood glucose levels maintained at 10.0 mmol/L (180 mg/dL) or higher. Hyperglycemia can activate the tissue factor pathway of coagulation, thereby setting the stage for enhanced thrombin formation and acute thrombosis.⁴⁶ Van den Berghe et al⁴⁷ found that by regulating hyperglycemia (maintaining blood glucose levels of 4.4–6.1 mmol/L [80–110 mg/dL]) through intensive insulin therapy, morbidity and mortality could be reduced.

	Hemostatic Abnormalities in Severe Sepsis and MODS

Top Abstract Systemic Inflammatory Response... Multiple Organ Dysfunction... Hemostatic Abnormalities in... Clinical Evaluation of Patients... Pharmacological Treatment of... Lessons Learned From the... Practical Bedside Application of... The Role of Critical... Conclusions References

 
Endothelial dysfunction and microvascular thrombosis appear to be particularly important factors in the development of MODS. In severe sepsis, a generalized inflammatory response is tightly linked to impaired fibrinolysis and excessive intravascular activation of coagulation. Generation and deposition of fibrin promotes formation of microvascular thrombi, which can compromise blood supply to tissues and organs, causing cellular injury and possibly organ dysfunction and death.^27,48,49 Studies with sensitive biomarkers of coagulation activation and fibrinolysis revealed impairments in these responses in nearly all patients with severe sepsis, and some of these abnormalities portend a poor prognosis.^49–54 Microvascular thrombosis occurs in both experimental models of sepsis and patients with sepsis.⁵⁵ Endothelial cells, which normally maintain homeostasis, contribute to abnormalities in coagulation and fibrinolysis through several mechanisms.

Abnormalities of Coagulation
Many patients with severe sepsis have abnormalities in coagulation due to direct stimulation of the coagulation cascade by cytokines, release of endogenous anticoagulants, and cellular injury. The result of the coagulation cascade is the formation of thrombin, which cleaves fibrinogen to form fibrin monomers, leading to the formation of a stable fibrin clot. Free thrombin also promotes clotting by directly activating platelets.

Whereas the extrinsic pathway of coagulation plays an important role in generating the initial hemostatic response to sepsis, the intrinsic pathway appears to amplify this response through cross-talk and feedback mechanisms.^56,57 Conversion of extrinsic and intrinsic clotting factors and amplification of coagulation by thrombin permits ongoing thrombosis.

In addition to their roles in coagulation responses and clot formation, coagulation factors also mediate systemic inflammation, potentially amplifying the septic process.⁵⁸ Thrombin and other activated clotting factors (eg, factor VIIa and the VIIa–tissue factor complex) can directly activate monocytes, macrophages, and endothelial cells, and thrombin can also stimulate multiple inflammatory pathways.^54,59 Effects of thrombin’s activities include enhanced recruitment of leukocytes, release of cytokines, and production of reactive oxygen species.⁵⁸ In turn, these effects contribute to progressive endothelial damage and ultimately deplete the antithrombotic potential of endothelial cells.

Therefore, derangements in clotting factors beget more inflammation, and this inflammation in turn promotes additional thrombosis. Fortunately, the body has endogenous regulatory mechanisms that normally prevent amplification of coagulation responses. These include circulating proteinase inhibitors such as proteins C and S, antithrombin, and tissue factor pathway inhibitor^.27

Protein C is a zymogen. In the presence of thrombin bound to thrombomodulin (a membrane receptor on the surface of endothelial cells that alters thrombin’s substrate specificity from fibrinogen to protein C), protein C is activated.⁵⁸ Activated protein C is generated roughly in proportion to the formation of thrombin and, in the presence of its cofactor protein S, acts as a feedback inhibitor of further thrombin generation by cleaving activated factors V and VIII.⁵⁷ In addition to its antithrombotic properties, activated protein C has anti-inflammatory and profibrinolytic properties,^10,60 which are discussed later.

Together with depletion of the plasma pool of protein C and the cytokine-induced downregulation of thrombomodulin, loss of protein C receptors on endothelial cells can interfere with protein C activation. When the activation of protein C is impaired, patients cannot benefit from the protective antithrombotic properties of the protein.

Abnormalities of Fibrinolysis
Endothelial cells are the principal source of tissue-type plasminogen activator, the primary enzyme responsible for activation of fibrinolysis through conversion of plasminogen to plasmin.^27,51 Plasminogen activator inhibitor 1, an endothelial cell product, is the primary inhibitor of both tissue-type plasminogen activator and urokinase-type plasminogen activator. The activity of plasminogen activator inhibitor 1 is limited by its binding to activated protein C, thus enhancing fibrinolysis.⁶¹ Additional inhibition of fibrinolysis occurs through the actions of ₂-antiplasmin and thrombin-activatable fibrinolysis inhibitor.^27,51 An imbalance between coagulation and fibrinolysis results, with suppression of fibrinolysis and the development of a procoagulant state.

	Clinical Evaluation of Patients With Severe Sepsis or MODS

Top Abstract Systemic Inflammatory Response... Multiple Organ Dysfunction... Hemostatic Abnormalities in... Clinical Evaluation of Patients... Pharmacological Treatment of... Lessons Learned From the... Practical Bedside Application of... The Role of Critical... Conclusions References

 
Despite compelling evidence for the pathogenesis of sepsis and the clinical progression to MODS, exact criteria for evaluating patients with known or suspected organ dysfunction have not been defined. Several scoring systems have been developed for this purpose and can be used to evaluate the need for and limitations of therapy.⁶² To date, these tools have been used primarily in evaluations of investigational agents, with substantial variation between clinical trials. Evaluation of disease severity generally involves assessment of several major organ systems for common indications of dysfunction in those organs^18,63–65 (Table 4).

Delirium, defined as a disturbance of consciousness characterized by an acute onset and fluctuating course of impaired cognitive functioning, is often an unrecognized complication that may cause communication difficulties with intubated patients.^67,68 Measures of cognitive dysfunction in patients receiving mechanical ventilation are strongly associated with both the success of attempts to extubate patients and length of stay in the hospital.^69,70 Early worsening of neurological capacity, coagulation, or renal function can portend a poor prognosis in patients with sepsis.⁷¹

	Pharmacological Treatment of Severe Sepsis

Top Abstract Systemic Inflammatory Response... Multiple Organ Dysfunction... Hemostatic Abnormalities in... Clinical Evaluation of Patients... Pharmacological Treatment of... Lessons Learned From the... Practical Bedside Application of... The Role of Critical... Conclusions References

 
Trials of anti-inflammatory treatment regimens for sepsis have had few successes.¹ However, results from recent studies have shown promise for the use of steroids in the treatment of patients with sepsis who have adrenal insufficiency.^72,73 In a small group of patients with sepsis and occult adrenal insufficiency, mortality was less (40%) in those treated with prednisolone (at the physiological dose) than in those treated with a placebo (55.6%).⁷² Additionally, Annane et al⁷³ found that treatment with hydrocortisone (50 mg every 6 hours) plus fludrocortisone (50 µg/day) reduced mortality in patients with refractory shock and relative adrenal insufficiency as determined with the short corticotropin test. Because the beneficial effect of these compounds is restricted to a particular subgroup of patients with sepsis, additional studies are needed to understand whether or not such therapy would be warranted in other subgroups of patients with severe sepsis.

Basic science and preclinical investigations indicate that the natural antithrombotics (activated protein C, antithrombin and tissue factor pathway inhibitor) can reduce mortality. However, although the results of phase 1 and phase 2 trials supported a therapeutic role for all of these substances, only treatment with drotrecogin alfa (activated) led to a reduction in 28-day mortality due to all causes in patients with severe sepsis in a phase 3 trial. Because drotrecogin alfa (activated) is the only approved pharmacological treatment for severe sepsis, the scientific basis for clinical trials with this agent and its role in the treatment of patients with severe sepsis are discussed next.

Activated Protein C
Seegers⁷⁴ was the first to identify and subsequently isolate protein C. When fractions with anticoagulant activity in complexes of prothrombin activated with thrombin were separated by using protein fractionation and chromatography, the third peak to elute on a diethylaminoethyl-cellulose column was named "protein C" (ie, A, B, . . .). Subsequent studies indicated that the molecule was a vitamin K–dependent glyco-protein that circulated as a zymogen. This inactive protein can be converted to a serine protease capable of membrane binding, and once activated by thrombin-antithrombin complexes, the protein exerts antithrombotic activity through the inactivation of coagulation factors Va and VIIIa.⁷⁵

  Biology.   An indirect anti-inflammatory property of activated protein C is suppression of generation of thrombin (Figure 3). In addition, activated protein C suppresses monocyte activation and production of proinflammatory cytokines such as IL-6, IL-1, and TNF- .^76–78 Through signaling mechanisms mediated by binding of cell-surface receptors, activated protein C limits the inflammatory response of endothelial cells to thrombin and blocks leukocyte adhesion to vascular endothelial cells, thus permitting leukocyte extravasation from vessels.^79,80 Activated protein C also promotes the lysis of microthrombi directly by neutralizing the activity of plasminogen activator inhibitor-1 and thus facilitating plasminogen activation and indirectly by limiting production of thrombin-activatable fibrinolysis inhibitor^81,82 (Figure 3).

View larger version (64K): [in this window] [in a new window]   Figure 3 Proposed mechanism of action of activated protein C. The cascade of events that lead to the prothrombotic, proinflammatory, and antifibrinolytic state in sepsis has multiple routes. Activated protein C has desirable effects at various points in this cascade. The anti-inflammatory effect of activated protein C is exerted through its ability to inhibit the production of inflammatory cytokines by monocytes and limit the adhesion and rolling of neutrophils and monocytes. It also inactivates various components of the coagulation cascade, namely factors Va and VIIIa, that normally lead to the formation of thrombin and eventual development of a fibrin clot. Additionally, by reducing the production of thrombin and the actions of plasminogen activator inhibitor-1 (PAI-1), activated protein C enhances the fibrinolytic system, allowing more rapid dissolution of fibrin clots.

  Clinical Studies.   The importance of the protein C system in sepsis is supported by observations that concentrations of protein C decline acutely and are severely depressed in patients with severe sepsis, imparting an increased risk of death.^52,84–89 Clinical studies indicated that the administration of protein C concentrate may improve outcomes of patients with severe sepsis, including patients with meningococcus-induced purpura fulminans.^90,91 Drotrecogin alfa (activated), a recombinant form of human activated protein C, produced dose-dependent reductions in plasma levels of markers of coagulation (D-dimers) and inflammation (serum IL-6) in a phase 2 study of patients with severe sepsis.⁹² The results of a phase 3 clinical trial, the PROWESS trial, further substantiated the role of recombinant activated protein C in significantly reducing mortality rates in patients with severe sepsis.¹⁰

	Lessons Learned From the PROWESS Trial

Top Abstract Systemic Inflammatory Response... Multiple Organ Dysfunction... Hemostatic Abnormalities in... Clinical Evaluation of Patients... Pharmacological Treatment of... Lessons Learned From the... Practical Bedside Application of... The Role of Critical... Conclusions References

 
The PROWESS trial was a randomized, double-blind, placebo-controlled, multicenter trial designed to evaluate whether treatment with drotrecogin alfa (activated) would reduce the rate of 28-day mortality due to all causes in patients with severe sepsis.¹⁰ A total of 164 centers in 11 countries enrolled eligible patients with the following criteria: known or suspected infection as indicated by clinical data at screening, 3 or 4 SIRS criteria according to ACCP/SCCM definitions, and sepsis-induced dysfunction of at least 1 organ system. Patients were randomized to receive treatment with placebo or drotrecogin alfa (activated), 24 µg/kg actual body weight per hour, for 96 hours.¹⁰

Patients were followed for 28 days after the start of the infusion or until death. They were monitored for changes in baseline characteristics, organ function, markers of disease severity, infection, hematological markers and other laboratory tests, adverse events, and changes in vital signs. The effects of treatment with drotrecogin alfa (activated) on serum IL-6 levels and plasma D-dimer levels were also evaluated.

The PROWESS trial was designed to enroll 2280 patients, but enrollment was suspended when a second interim analysis indicated a significant difference in mortality rates between the drotrecogin alfa (activated) group and the placebo group. Subjects were comparable by groups with respect to demographic variables and distribution of important indicators of disease severity; approximately 75% of patients had at least 2 dysfunctional organ systems at the time of enrollment.¹⁰ The study results revealed a significant difference in 28-day mortality rates: 30.8% in 840 patients treated with placebo and 24.7% in 850 patients treated with drotrecogin alfa (activated) (P = .005). This difference in the rate of mortality due to all causes was associated with an absolute reduction in the risk of death of 6.1% (P =.005) and a reduction in the relative risk of death of 19.4% (95% CI, 6.6–30.5). The drotrecogin alfa (activated) and placebo groups also were remarkably similar in the time (mean [SD]) from detection of the first organ dysfunction to the initiation of treatment (17.5 [12.8] vs 17.4 [9.1] hours, respectively).

Compared with patients in the placebo group, patients receiving drotrecogin alfa (activated) had greater decreases in plasma levels of D-dimer during the first 7 days after initiation of the infused treatment. Treatment with drotrecogin alfa (activated) also decreased IL-6 levels, consistent with the drug’s known anti-inflammatory effects. Despite these differences in plasma markers of coagulation and inflammation, the drotrecogin alfa (activated) and placebo groups had comparable prevalences of thrombotic events (2.0% and 3.0%, respectively; P = .20) and new infections (25.5% and 25.1%, respectively; P = .85).

Because it is a natural antithrombotic, treatment with drotrecogin alfa (activated) versus placebo was associated with increased bleeding (3.5% vs 2.0%, respectively; P = .06).¹⁰ Serious bleeding typically was due to injury to a vessel and predominantly occurred during the infusion period in those patients who underwent medically invasive procedures.⁹³

During the PROWESS trial, no significant differences were found between the drotrecogin alfa (activated) and placebo groups in mean hospital costs (P = .72) or resource use (P .22) (excluding the cost of the drotrecogin alfa [activated]).⁹⁴ These data, along with those recently published by Manns et al,⁹⁵ show that when used as indicated on the product label in patients with severe sepsis and an increased risk of death (eg, Acute Physiology and Chronic Health Evaluation II score 25), drotrecogin alfa (activated) has a cost-effectiveness profile similar to that of common medical treatments.^94,95 Careful selection of patients is important to maintain this profile; cost-effectiveness declines in patients with a poor long-term life expectancy.^94,95 Consideration for treatment with drotrecogin alfa (activated) should be based on the PROWESS trial’s inclusion criteria for severe sepsis, consensus agreement for aggressive therapy, and safety issues concerning treatment with an antithrombotic compound.⁹³

For drotrecogin alfa (activated), the number needed to treat was 16; that is, for every 16 patients treated with drotrecogin alfa (activated), 1 life will be saved. These results are comparable to those of other commonly accepted interventions, and drotrecogin alfa (activated) is now licensed by the Food and Drug Administration.

	Practical Bedside Application of PROWESS: Who Do We Treat With Drotrecogin Alfa (Activated)?

Top Abstract Systemic Inflammatory Response... Multiple Organ Dysfunction... Hemostatic Abnormalities in... Clinical Evaluation of Patients... Pharmacological Treatment of... Lessons Learned From the... Practical Bedside Application of... The Role of Critical... Conclusions References

 
Selection criteria for patients included in the PROWESS trial have provided a basic guideline for clinicians and nurses to use in practice. Patients in the PROWESS trial were selected if they met the following criteria: (1) known or suspected infection, (2) presence of at least 3 signs of systemic inflammation, and (3) sepsis-induced dysfunction of at least 1 organ or system that lasted no longer than 24 hours. The preceding criteria were developed to specifically define a population with severe sepsis.

Using detailed subgroup analysis of the PROWESS data,⁹⁶ the FDA has determined that drotrecogin alfa (activated) is most appropriately used in adult patients with severe sepsis who are at a high risk of death (eg, as determined by APACHE II score). Alternatively, European regulatory authorities have used 2 organ dysfunctions as a criterion for increased risk of death for patients with severe sepsis being considered for treatment with drotrecogin alfa (activated). Although the APACHE II score is helpful in determining severity of illness, it can be difficult to translate from a strict clinical trial setting into practice at the bedside. In fact, few physicians use it to determine eligibility for treatment of a patient with sepsis. Therefore, a clinical surrogate such as cardiovascular dysfunction characterized by vasopressor dependency despite adequate fluid resuscitation or simply using 2 concurrent sepsis-induced organ dysfunctions could be a more practical approach to determining who will most likely benefit from treatment with drotrecogin alfa (activated). These patients are considered to be at a high risk of death because of the increase in mortality seen in this population. This approach allows the clinician to define a population that is at a high risk of death and would therefore most likely benefit from treatment.

	The Role of Critical Care Nurses

Top Abstract Systemic Inflammatory Response... Multiple Organ Dysfunction... Hemostatic Abnormalities in... Clinical Evaluation of Patients... Pharmacological Treatment of... Lessons Learned From the... Practical Bedside Application of... The Role of Critical... Conclusions References

 
Critical care nurses play a vital role in recognizing and managing patients with severe sepsis. By being aware of SIRS criteria and clinical indicators of sepsis, critical care nurses can promote prompt diagnosis and treatment of developing sepsis. Early recognition and management of MODS is essential to prevent escalating mortality rates in patients with severe sepsis.

A number of nursing care measures can be used to assess, monitor, and treat patients with severe sepsis (Table 5).⁹⁷ These include monitoring vital signs, changes in cardiovascular and hemodynamic parameters, ventilatory and oxygenation status, renal function, coagulation parameters, metabolic indices, and mental status.⁹⁸ In addition, providing comprehensive treatment of sepsis, including organ system support for patients with MODS, and monitoring and reporting responses to therapies are essential aspects of nursing care.

	Conclusions

Top Abstract Systemic Inflammatory Response... Multiple Organ Dysfunction... Hemostatic Abnormalities in... Clinical Evaluation of Patients... Pharmacological Treatment of... Lessons Learned From the... Practical Bedside Application of... The Role of Critical... Conclusions References

 
In patients with severe sepsis, the overwhelming systemic inflammation indicated by SIRS criteria is associated with organ dysfunction and the possible development of MODS. Although the etiology of MODS is multifactorial, disturbed homeostasis with endothelial cell dysfunction and a prothrombotic diathesis in the microcirculation appear to play a major role. Drotrecogin alfa (activated) has antithrombotic, anti-inflammatory, and profibrinolytic properties, but the exact mechanism that results in reduced mortality due to severe sepsis as occurred in the recently concluded PROWESS trial is unknown. Treatment with drotrecogin alfa (activated) produced a significant decrease in 28-day mortality due to all causes in patients with severe sepsis, with an acceptable safety profile in the population of patients enrolled in the PROWESS trial. The results of the PROWESS trial indicate that drotrecogin alfa (activated) can decrease manifestations of systemic inflammation reflected in the SIRS criteria and can decrease morbidity and mortality associated with sepsis-induced MODS. Critical care nurses play an important role in recognizing patients at risk for sepsis, recognizing the development of MODS, and helping to manage important aspects of treatment for patients with severe sepsis. Knowledge of treatment advances, including the use of drotrecogin alfa (activated), will facilitate optimal care delivery for patients with severe sepsis.

	ACKNOWLEDGMENTS

 
Dr Ely is an advisor to and a recipient of a grant from Eli Lilly & Co. Dr Ely is a recipient of the Pharmacology in Aging Grant from the American Federation for Aging Research and the Paul Beeson Faculty Scholar Award from the Alliance for Aging Research. He is a recipient of a K23 from the National Institutes of Health (AG01023–01A1) and is associate director of research for the Veterans Administration Geriatric Research Education and Clinical Center. Dr Kleinpell is a member of the National Speakers Bureau of Eli Lilly. Dr Goyette is a consultant with Eli Lilly and an advisor to the National Initiative in Sepsis Education.

To purchase reprints, contact The InnoVision Group, 101 Columbia, Aliso Viejo, CA 92656. Phone, (800) 809-2273 or (949) 362-2050 (ext 532); fax, (949) 362-2049; e-mail, reprints{at}aacn.org.

	REFERENCES

Top Abstract Systemic Inflammatory Response... Multiple Organ Dysfunction... Hemostatic Abnormalities in... Clinical Evaluation of Patients... Pharmacological Treatment of... Lessons Learned From the... Practical Bedside Application of... The Role of Critical... Conclusions References

 

1. Zeni F, Freeman B, Natanson C. Anti-inflammatory therapies to treat sepsis and septic shock: a reassessment. Crit Care Med. 1997;25:1095–1100.[Medline]
2. Natanson C, Esposito CJ, Banks SM. The sirens’ songs of confirmatory sepsis trials: selection bias and sampling error. Crit Care Med. 1998;26:1927–1931.[Medline]
3. Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med. 2001;29:1303–1310.[Medline]
4. Angus DC, Kelley MA, Schmitz RJ, White A, Popovich J Jr. Caring for the critically ill patient: current and projected workforce requirements for care of the critically ill and patients with pulmonary disease: can we meet the requirements of an aging population? JAMA. 2000;284:2762–2770.[Abstract/Free Full Text]
5. Buerhaus PI, Staiger DO, Auerbach DI. Why are shortages of hospital RNs concentrated in specialty care units? Nurs Econ. 2000;18:111–116.[Medline]
6. Wheeler AP, Bernard GR. Treating patients with severe sepsis. N Engl J Med. 1999;340:207–214.[Free Full Text]
7. Friedman G, Silva E, Vincent JL. Has the mortality of septic shock changed with time? Crit Care Med. 1998;26:2078–2086.[Medline]
8. Bone RC, Balk RA, Cerra FB, et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest. 1992;101:1644–1655.[Abstract/Free Full Text]
9. Opal SM, Cross AS. Clinical trials for severe sepsis: past failures, and future hopes. Infect Dis Clin North Am. 1999;13:285–297.[Medline]
10. Bernard GR, Vincent JL, Laterre PF, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med. 2001;344:699–709.[Abstract/Free Full Text]
11. Trzeciak S, Zanotti S, Dellinger RP, Parrillo JE. Inclusion criteria for clinical trials in sepsis 1976–2001: did the ACCP/SCCM Consensus Conference definitions make a difference? [abstract]. Available at: http://www.abstracts-on-line.com/abstracts/ATS/. Accessed November 8, 2002.
12. Teplick R, Rubin R. Therapy of sepsis: why have we made such little progress? Crit Care Med. 1999;27:1682–1683.[Medline]
13. Vincent JL. Dear SIRS, I’m sorry to say that I don’t like you . . . Crit Care Med. 1997;25:372–374.[Medline]
14. Levy M. The challenge of sepsis: epidemiology and definitions. Paper presented at: Society of Critical Care Medicine Annual Meeting; January 30, 2002; San Diego, Calif.
15. Vincent JL, De Mendonca A, Cantraine F, et al. Use of the SOFA score to assess the incidence of organ dysfunction/failure in intensive care units: results of a multicenter, prospective study. Working group on "sepsis-related problems" of the European Society of Intensive Care Medicine. Crit Care Med. 1998;26:1793–1800.[Medline]
16. Rangel-Frausto MS, Pittet D, Costigan M, Hwang T, Davis CS, Wenzel RP. The natural history of the systemic inflammatory response syndrome (SIRS): a prospective study. JAMA. 1995;273:117–123.[Abstract]
17. Marshall JC, Cook DJ, Christou NV, Bernard GR, Sprung CL, Sibbald WJ. Multiple organ dysfunction score: a reliable descriptor of a complex clinical outcome. Crit Care Med. 1995;23:1638–1652.[Medline]
18. Balk RA. Pathogenesis and management of multiple organ dysfunction or failure in severe sepsis and septic shock. Crit Care Clin. 2000;16:337–352.[Medline]
19. Ferreira FL, Bota DP, Bross A, Melot C, Vincent JL. Serial evaluation of the SOFA score to predict outcome in critically ill patients. JAMA. 2001;286:1754–1758.[Abstract/Free Full Text]
20. Balk RA, Goyette RE. The multiple organ dysfunction syndrome in patients with severe sepsis: more than just inflammation. In: Balk RA, ed. Advances in the Diagnosis and Management of the Patient With Severe Sepsis. London, England: The Royal Society of Medicine Press Ltd; 2002:39–60.
21. Ely EW, Wheeler AP, Thompson BT, Ancukiewicz M, Steinberg KP, Bernard GR. Recovery rate and prognosis in older persons who develop acute lung injury and the acute respiratory distress syndrome. Ann Intern Med. 2002;136:25–36.[Abstract/Free Full Text]
22. Waterer GW, Quasney MW, Cantor RM, Wunderink RG. Septic shock and respiratory failure in community-acquired pneumonia have different TNF polymorphism associations. Am J Respir Crit Care Med. 2001;163:1599–1604.[Abstract/Free Full Text]
23. Mira JP, Cariou A, Grall F, et al. Association of TNF2, a TNF-promoter polymorphism, with septic shock susceptibility and mortality: a multicenter study. JAMA. 1999;282:561–568.[Abstract/Free Full Text]
24. Westendorp RG, Langermans JA, Huizinga TW, Verweij CL, Sturk A. Genetic influence on cytokine production in meningococcal disease. Lancet. 1997;349:1912–1913.[Medline]
25. Angele MK, Xu YX, Ayala A, et al. Gender dimorphism in trauma-hemorrhage-induced thymocyte apoptosis. Shock. 1999;12:316–322.[Medline]
26. Pinsky MR, Vincent JL, Deviere J, Alegre M, Kahn RJ, Dupont E. Serum cytokine levels in human septic shock: relation to multiple-system organ failure and mortality. Chest. 1993;103:565–575.[Abstract/Free Full Text]
27. Iba T, Kidokoro A, Yagi Y. The role of the endothelium in changes in procoagulant activity in sepsis. J Am Coll Surg. 1998;187:321–329.[Medline]
28. Astiz ME, Rackow EC. Septic shock. Lancet. 1998;351:1501–1505.[Medline]
29. Hinshaw LB. Sepsis/septic shock: participation of the microcirculation—an abbreviated review. Crit Care Med. 1996;24:1072–1078.[Medline]
30. Steurer G, Yang P, Rao V, Mohl W, Glogar D, Smetana R. Acute myocardial infarction, reperfusion injury, and intravenous magnesium therapy: basic concepts and clinical implications. Am Heart J. 1996;132:478–482.[Medline]
31. Baskurt OK, Temiz A, Meiselman HJ. Red blood cell aggregation in experimental sepsis. J Lab Clin Med. 1997;130:183–190.[Medline]
32. Rosser DM, Manji M, Cooksley H, Bellingan G. Endotoxin reduces maximal oxygen consumption in hepatocytes independent of any hypoxic insult. Intensive Care Med. 1998;24:725–729.[Medline]
33. Szabo A, Salzman AL, Szabo C. Poly (ADP-ribose) synthetase activation mediates pulmonary microvascular and intestinal mucosal dysfunction in endotoxin shock. Life Sci. 1998;63:2133–2139.[Medline]
34. Yu P, Martin CM. Increased gut permeability and bacterial translocation in Pseudomonas pneumonia-induced sepsis. Crit Care Med. 2000;28:2573–2577.[Medline]
35. Pinsky MR. Pro- and anti-inflammatory balance in sepsis. Curr Opin Crit Care. 2000;6:411–415.
36. Rosenbloom AJ, Pinsky MR, Napolitano C, et al. Suppression of cytokine-mediated ß₂-integrin activation on circulating neutrophils in critically ill patients. J Leukoc Biol. 1999;66:83–89.[Abstract]
37. Blackwell TS, Christman JW. Sepsis and cytokines: current status. Br J Anaesth. 1996;77:110–117.[Abstract/Free Full Text]
38. Christman JW, Holden EP, Blackwell TS. Strategies for blocking the systemic effects of cytokines in the sepsis syndrome. Crit Care Med. 1995;23:955–963.[Medline]
39. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network. N Engl J Med. 2000;342:1301–1308.[Abstract/Free Full Text]
40. Eisner MD, Thompson T, Hudson LD, et al. Efficacy of low tidal volume ventilation in patients with different clinical risk factors for acute lung injury and the acute respiratory distress syndrome. Am J Respir Crit Care Med. 2001;164:231–236.[Abstract/Free Full Text]
41. Moore FA, Moore EE, Sauaia A. Blood transfusion: an independent risk factor for postinjury multiple organ failure. Arch Surg. 1997;132:620–624.[Abstract]
42. Hudson LD, Milberg JA, Anardi D, Maunder RJ. Clinical risks for development of the acute respiratory distress syndrome. Am J Respir Crit Care Med. 1995;151:293–301.[Abstract]
43. Ranieri VM, Suter PM, Tortorella C, et al. Effect of mechanical ventilation on inflammatory mediators in patients with acute respiratory distress syndrome: a randomized controlled trial. JAMA. 1999;282:54–61.[Abstract/Free Full Text]
44. Tremblay L, Valenza F, Ribeiro SP, Li J, Slutsky AS. Injurious ventilatory strategies increase cytokines and c-fos m-RNA expression in an isolated rat lung model. J Clin Invest. 1997;99:944–952.[Medline]
45. Dreyfuss D, Saumon G. Ventilator-induced lung injury: lessons from experimental studies. Am J Respir Crit Care Med. 1998;157:294–323.
46. Rao AK, Chouhan V, Chen X, Sun L, Boden G. Activation of the tissue factor pathway of blood coagulation during prolonged hyperglycemia in young healthy men. Diabetes. 1999;48:1156–1161.[Abstract]
47. vandenBerghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in the critically ill patients. N Engl J Med. 2001;345:1359–1367.[Abstract/Free Full Text]
48. Gando S, Kameue T, Nanzaki S, Nakanishi Y. Disseminated intravascular coagulation is a frequent complication of systemic inflammatory response syndrome. Thromb Haemost. 1996;75:224–228.[Medline]
49. Kidokoro A, Iba T, Fukunaga M, Yagi Y. Alterations in coagulation and fibrinolysis during sepsis. Shock. 1996;5:223–228.[Medline]
50. Levi M, ten Cate H. Disseminated intravascular coagulation. N Engl J Med. 1999;341:586–592.[Free Full Text]
51. Vervloet MG, Thijs LG, Hack CE. Derangements of coagulation and fibrinolysis in critically ill patients with sepsis and septic shock. Semin Thromb Hemost. 1998;24:33–44.[Medline]
52. Lorente JA, Garcia-Frade LJ, Landin L, et al. Time course of hemostatic abnormalities in sepsis and its relation to outcome. Chest. 1993;103:1536–1542.[Abstract/Free Full Text]
53. Carvalho AC, Freeman NJ. How coagulation defects alter outcome in sepsis: survival may depend on reversing procoagulant conditions. J Crit Illness. 1994;9:51–75.
54. Tapper H, Herwald H. Modulation of hemostatic mechanisms in bacterial infectious diseases. Blood. 2000;96:2329–2337.[Free Full Text]
55. Topalan M, Arinci A, Olgac V, Kaygusuz A, Erer M. Effect of distant septic foci on the patency of microvascular anastomoses. J Reconstr Microsurg. 2000;16:297–301.[Medline]
56. Levi M, ten Cate H, van der Poll T, van Deventer SJ. Pathogenesis of disseminated intravascular coagulation in sepsis. JAMA. 1993;270:975–979.[Abstract]
57. Rosenberg RD, Aird WC. Vascular bed-specific hemostasis and hypercoagulable states. N Engl J Med. 1999;340:1555–1564.[Free Full Text]
58. Esmon CT. Inflammation and thrombosis: mutual regulation by protein C. Immunologist. 1998;6:84–89.
59. Esmon CT. The endothelial cell protein C receptor. Thromb Haemost. 2000;83:639–643.[Medline]
60. Joyce DE, Gelbert L, Ciaccia A, DeHoff B, Grinnell BW. Gene expression profile of antithrombotic protein C defines new mechanisms modulating inflammation and apoptosis. J Biol Chem. 2001;276:11199–11203.[Abstract/Free Full Text]
61. Hesselvik JF, Malm J, Dahlback B, Blomback M. Protein C, protein S and C4b-binding protein in severe infection and septic shock. Thromb Haemost. 1991;65:126–129.[Medline]
62. Vincent JL, Ferreira F, Moreno R. Scoring systems for assessing organ dysfunction and survival. Crit Care Clin. 2000;16:353–366.[Medline]
63. Marshall JC. Organ dysfunction as an outcome measure in clinical trials. Eur J Surg Suppl. 1999;62–67.
64. Baue AE. History of MOF and definitions of organ failure. In: Baue AE, Faist E, Fry DE, eds. Multiple Organ Failure: Pathophysiology, Prevention, and Therapy. New York, NY: Springer-Verlag New York Inc; 2000:3–13.
65. Papadopoulos MC, Davies DC, Moss RF, Tighe D, Bennett ED. Pathophysiology of septic encephalopathy: a review. Crit Care Med. 2000;28:3019–3024.[Medline]
66. Eidelman LA, Putterman D, Putterman C, Sprung CL. The spectrum of septic encephalopathy: definitions, etiologies, and mortalities. JAMA. 1996;275:470–473.[Abstract]
67. Ely EW, Inouye SK, Bernard GR, et al. Delirium in mechanically ventilated patients: validity and reliability of the confusion assessment method for the intensive care unit (CAM-ICU). JAMA. 2001;286:2703–2710.[Abstract/Free Full Text]
68. Ely EW, Siegel MD, Inouye SK. Delirium in the intensive care unit: an under-recognized syndrome of organ dysfunction. Semin Respir Crit Care Med. 2001;22:115–126.[Medline]
69. Namen AM, Ely EW, Tatter SB, et al. Predictors of successful extubation in neurosurgical patients. Am J Respir Crit Care Med. 2001;163:658–664.