Sepsis is defined as a systemic inflammatory response to infection (TABLE 1).¹ The clinical presentation of the septic patient is described as the systemic inflammatory response syndrome (SIRS), which can include alterations in body temperature, heart and respiratory rates, and white blood cell count. Evolving inflammatory responses can ultimately trigger a number of pathophysiological alterations that lead to severe sepsis, which is defined as sepsis with the additional complication of organ dysfunction.

The clinical continuum from sepsis to severe sepsis is associated with increasing morbidity and mortality. According to the National Center for Health Statistics, septicemia (an older term defined as the presence of microorganisms and/or their toxins in the blood) was the tenth leading cause of death in the United States in 1999.² In regard to severe sepsis, recent estimates indicate that over 750,000 cases occur in the United States annually, with mortality rates ranging from 10% in children to almost 40% in the elderly.³ Given the high level of care required for these patients, costs of severe sepsis are estimated to be over $16 billion annually.³

This article will examine the clinical presentation of the severe sepsis patient, discuss current concepts in the pathophysiology of severe sepsis, review basic principles of sepsis and severe sepsis treatment, and discuss the pharmacology and therapeutics of drotrecogin alfa (activated) (Xigris), a recombinant form of human activated protein C recently approved for the treatment of severe sepsis.

The Clinical Presentation of Severe Sepsis
A 62-year-old female with a history of type 2 diabetes mellitus and hypertension was admitted to a trauma center following an automobile accident. Examination revealed blunt thoracic and abdominal trauma and a fractured right femur. The patient was dyspneic, tachycardic, hypotensive, and her skin was pale and cool. A right-sided hemothorax was managed by chest tube insertion. Imaging studies, along with exploratory surgery, revealed extensive trauma and bleeding within the abdominal cavity. Surgical management of the abdominal hemorrhage and the fractured femur resulted in significant improvement in vital signs, and the patient was moved to the ICU.

Four days later, the patient became febrile and her WBC count was elevated with increased immature forms. Sepsis was immediately suspected, broad-spectrum IV antibiotic therapy was initiated, and blood cultures were obtained. During the following 24-48 hours, the patient experienced increasing respiratory distress and hypotension. Urine output decreased and the serum creatinine and BUN were elevated. Deteriorating blood gases necessitated intubation and mechanical ventilation. The patient was determined to be in severe sepsis.

The above case study depicts a number of clinical features commonly observed in the natural history of sepsis and severe sepsis. Although Gram-positive bacteria and fungal organisms can cause sepsis, most cases result from Gram-negative pathogens, such as Escherichia coli, Enterobacter spp., and Pseudomonas aeruginosa.⁴ A number of factors can disrupt barriers and/or impair defense mechanisms that normally prevent or limit Gram-negative bacteremia. Trauma to the gastrointestinal tract, perforation, or surgery, debilitating conditions such as diabetes mellitus, use of invasive procedures and devices in the intensive care setting, and treatment with immunosuppressant drugs increase the susceptibility of patients to Gram-negative sepsis. Endotoxin, a component of Gram-negative bacterial cell walls, is a potent stimulus of cytokine release by macrophages. There is strong evidence that cytokines play a major role in the development of sepsis and facilitate many of the pathophysiological changes that mark the progression from sepsis to severe sepsis.⁵

Pathophysiology of Severe Sepsis
A number of chemical mediators are released during the inflammatory response to infection or trauma. Major proinflammatory mediators include specific cytokines, such as TNF-a and IL-1b, chemo-kines, prostaglandins, and platelet-activating factor. Proinflammatory mediators facilitate clearance of the injuring stimulus, promote resolution of injury, and are involved in processing of damaged tissue. In order to control the intensity and duration of the inflammatory response, anti-inflammatory mediators are released that act to regulate the synthesis, release, and actions of proinflammatory mediators. Examples of anti-inflammatory mediators are IL-4 and TGF-b. The balance between proinflammatory actions and compensatory anti-inflammatory mediator activity restricts inflammation to local sites of injury, prevents significant systemic inflammatory responses, and minimizes the poten tial adverse effects of proinflammatory mediators on host tissue.⁵

In the setting of mild to moderate infection or trauma, particularly in patients who do not have preexisting debilitating conditions, the homeostasis between proinflammatory and anti-inflammatory activity is well maintained. These patients are less likely to develop extensive systemic inflammatory responses and are at low risk for developing organ dysfunction. However, patients with severe infectious or traumatic insults may begin to experience an imbalance between proinflammatory and anti-inflammatory effects that sets the stage for sepsis and its progression to severe sepsis.^5,6 Patients who are debilitated and/or immunocompromised are further predisposed to loss of balance between proinflammatory and anti-inflammatory activity, even in the face of mild infection or trauma.

One of the first indications of altered proinflammatory/anti-inflammatory balance and the emergence of sepsis is the development of SIRS. The clinical manifestations of SIRS result from a massive level of proinflammatory mediator activity that "spills over" from local sites of injury into the systemic circulation.⁵ SIRS can present with fever or hypothermia, tachycardia, tachypnea, and leukocytosis or leukopenia (TABLE 1). In addition to SIRS, the intense proinflammatory response can precipitate a number of pathophysiological alterations that lead to the development of severe sepsis. Major alterations include increased vascular permeability, vasodilation, platelet activation and aggregation, activation of the coagulation cascade, and defects in coagulation control mechanisms, including defic-iencies in protein C and protein S activities.⁷ Increased vascular permeability and vasodilation results in severe hypotension (septic shock) that is often resistant to fluid resuscitation and requires vasopressors and/or inotropic agents. The impaired blood flow due to platelet activation and hypercoagulability causes diffuse ischemia and hypoxia. Taken together, these pathophysiological changes lead to hallmarks of severe sepsis: progressive organ hypoperfusion and the development of a multiple organ dysfunction syndrome (MODS).⁵

Altered homeostasis between proinflammatory and anti-inflammatory activity can also involve a large-scale anti-inflammatory response that overcompensates for the degree of systemic inflammation in the patient. This phenomenon is described as the compensatory anti-inflammatory response syndrome (CARS) and can result in significant suppression of immune function, including a reduction in proinflammatory cytokine secretion.⁵ The immune suppression associated with CARS further complicates sepsis by prohibiting recovery from the initial insult and increasing susceptibility to infection.⁵ A summary of the pathophysiology of severe sepsis, including the concept of impaired proinflammatory and anti-inflammatory homeostasis, is shown in FIGURE 1.

Table 1: Definitions of Sepsis-Related Terms
Sepsis	A systemic inflammatory response to infection
Severe sepsis	Sepsis with one or more dysfunctional organs or systems (e.g., cardiovascular dysfunction as indicated by hypotension and shock that is resistant to fluid resuscitation, respiratory dysfunction as indicated by hypoxemia, renal dysfunction as indicated by anuria or oliguria)
Systemic inflammatory response syndrome (SIRS)	A syndrome in which inflammatory mediator release, particularly cytokines such as TNF, secondary to an infectious and/or traumatic insult, causes the patient to present with at least two of the following conditions: ?i> alterations in body temperature (>38°C or <36°C) ?heart rate >90 beats/min ?i> alterations in respiratory function (rate >20 breaths/min or PaCO2 <32 mmHg) ?i> alterations in WBC count (>12,000/mm3 or <4,000/mm3 or >10% immature forms)
Compensatory anti-inflammatory response syndrome (CARS)	A syndrome in which anti-inflammatory mediator release overcompensates for the systemic inflammatory response to an infectious and/or traumatic insult leading to a state of immune suppression, increased susceptibility of the critically ill patient to infection, and impaired recovery
Septic shock	Severe sepsis with hypotension that is resistant to fluid resuscitation and requires pharmacological intervention (vasopressors and/or inotropic agents)
Multiple organ dysfunction syndrome (MODS)	A syndrome in which the hypotension and hypoperfusion, secondary to the pathophysiological alterations in severe sepsis, result in dysfunction in more than one organ or system

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Basic Principles of Sepsis
A major goal in the management of sepsis is rapid eradication of infection. Empiric antimicrobial therapy is instituted as soon as possible. In adults with suspected bacterial sepsis, antibiotics with broad-spectrum coverage, such as imipenem/cilastatin (Primaxin) or meropenem (Merrem), are possible choices.⁴ Blood cultures and identification of sources of infection—such as wounds from trauma or surgery, invasive devices, or indwelling catheters—will help in identifying specific pathogens and selecting an antimicrobial.

As sepsis progresses to severe sepsis with accompanying septic shock, increasing emphasis is placed on hemodynamic support in addition to managing the infection.⁸ Adequate tissue oxygenation is important, and mechanical ventilation may be required. Blood pressure and organ perfusion are supported with fluid therapy and/or pharmacological agents, such as inotropic and vasopressor drugs. Fluid resuscitation with crystalloid solutions, such as normal saline or lactated Ringer solution, is a common approach. If hypotension persists despite aggressive fluid therapy, pharmacological approaches are considered, including administration of dopamine, dobutamine, and norepinephrine. Dopamine is often preferred due to its dose-dependent ability to increase systemic vascular resistance, increase cardiac output, and enhance renal perfusion.

Figure 1: The Pathophysiology of Severe Sepsis

Management of Severe Sepsis
The management of severe sepsis is a challenging task for the clinician. Historically, treatment has been limited to managing the infection and hemodynamic support. The development of therapeutic agents that could significantly reduce mortality from severe sepsis has been unsuccessful. However, our understanding of the pathophysiology of severe sepsis has evolved considerably over the last decade, and this has yielded some promising pharmacological targets.

Use of Drotrecogin alfa (activated) [Xigris]
Drotrecogin alfa (activated) is a recombinant form of human activated protein C. Approved by the FDA in November 2001, it is indicated for the reduction of mortality in adult patients with severe sepsis who have a high risk of death (TABLE 2). Drotrecogin alfa (activated) is the first agent approved specifically for the treatment of sepsis. Currently, this agent is only approved for use in adults since there is no trial data in pediatric populations.

Pharmacology: Activated protein C is an endogenous proteolytic enzyme that cleaves clotting factors Va and VIIIa. The conversion of protein C to activated protein C is mediated by thrombin that is bound to thrombomodulin on the surface of vascular endo- thelial cells. In this manner, activated protein C serves as a physiological modulator of the coagulation cascade.⁹ In addition to clotting factor degradation, there is evidence that activated protein C promotes fibrinolysis by inhibiting plasminogen activator inhibitor-1 (PAI-1), an endothelial-derived molecule that prevents tissue-type plasminogen activator (t-PA) from binding to fibrin. Activated protein C thereby promotes clot dissolution by facilitating a greater level of t-PA activity.⁹

Finally, there is evidence that activated protein C may have anti-inflammatory actions based on its ability to inhibit cytokine release by activated monocytes in vitro.^9,10 The initial rationale for investigating the role of activated protein C as a therapeutic agent was based on the protein C deficiency and procoagulant state associated with severe sepsis.^7,11 However, it is not clear whether the anticoagulant and profibrinolytic properties of activated protein C are the only pharmacological actions responsible for the therapeutic response in severe sepsis.

Clinical Trial Data and Efficacy: The efficacy and safety of activated protein C in the treatment of severe sepsis were examined through a randomized, double-blind, placebo-controlled, multicenter study entitled the Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial.¹¹ Selection criteria for this Phase III trial included known or suspected infection, three or more signs of systemic inflammation, and evidence of acute dysfunction in at least one organ or system. Patients were randomized to receive either intravenous drotrecogin alfa (activated) infusion at 24 mcg/kg/hr for 96 hours or placebo infusion and subsequently followed for a period of 28 days or until death. The primary end point of the PROWESS trial was death. In addition, specific subgroups were stratified based on specific parameters such as overall risk of death, gender, numbers of organs or systems that were dysfunctional, nature and site of infection, and documented protein C deficiency before initiation of treatment. Risk of death was assessed using the Acute Physiology and Chronic Health Evaluation II (APACHE II) score. The APACHE II score is a tool to predict mortality of critically ill patients.¹² In general, the higher the APACHE II score, the greater the risk of patient death.

The PROWESS trial demonstrated a lower mortality rate for severe sepsis patients treated with drotrecogin alfa (activated) (24.7%) compared to placebo infusion (30.8%). This translated to a 19.4% reduction in the relative risk of death. Detailed analysis of stratified subgroups revealed a 13% reduction in mortality for severe sepsis patients with a high risk of death (APACHE II scores >25); however, there was not a significant reduction in mortality for patients with lower risk of death (APACHE II scores <25). In addition, the greater the number of dysfunctional organs or systems in the patient, the greater the absolute reduction in mortality.

Interestingly, severe sepsis patients without protein C deficiency before initiation of treatment also experienced a significant reduction in mortality, which suggests that drotrecogin alfa (activated) has pharmacological benefit other than that derived from solely replacing protein C in the patient. In-vitro studies have previously demonstrated anti-inflammatory actions of activated protein C, including inhibition of cytokine secretion from lipopolysaccharide-stimulated monocytes.¹⁰ The finding from the PROWESS trial that drotrecogin alfa (activated) decreased serum IL-6 levels in severe sepsis patients provided additional evidence for anti-inflammatory properties.

Table 2: A Synopsis of Drotrecogin alfa (activated) [Xigris]
Origin	Drotrecogin alfa (activated), manufactured and marketed by Eli Lilly and Company under the brand name Xigris, is recombinant human activated protein C derived from the expression of cDNA encoding human inactive protein C followed by thrombin-mediated cleavage to the active form
Approved indication	Approved in November 2001 for the reduction in mortality in adult patients with severe sepsis who have a high risk of death (as determined by an Acute Physiology and Chronic Health Evaluation II [APACHE II] score of >25)
Possible pharmacological properties	(1) Antithrombotic properties: anticoagulant activity through cleavage of factors Va and VIIIa and fibrinolytic activity through inhibition of plasminogen activator inhibitor-1 (PAI-1) (2) Anti-inflammatory properties (e.g., inhibition of cytokine release)
How supplied and storage	Available in 5-mg and 20-mg single-use vials containing sterile, preservative-free, lyophilized drotrecogin alfa (activated); (store at 2?to 8°C protected from light)
Dosage and administration	Intravenous infusion at 24 mcg/kg/hr for 96 hours through a dedicated peripheral intravenous line or through a dedicated lumen of a central venous catheter

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Adverse Reactions, Warnings, and Contraindications: The only major adverse reaction to drotrecogin alfa (activated) observed in the PROWESS trial was bleeding.^11,13 At least one bleeding event was observed in 25% of drotrecogin alfa (activated)-treated patients during the 28-day study, compared to 18% of placebo-treated patients. However, serious, life-threatening bleeding events were identified in 3.5% of drotrecogin alfa (activated)-treated patients compared to 2.0% for those given a placebo infusion. Most of the bleeding events were observed during the initial 96-hour infusion period. Hemorrhage sites included gastrointestinal, abdominal cavity, thoracic cavity, retroperitoneal, intracranial, genitourinary, skin, and soft tissue. In some cases, bleeding events required administration of multiple units of packed red cells. The majority of the patients who experienced bleeding were predisposed to hemorrhage by conditions such as trauma, gastrointestinal tract ulceration, or severe coagulopathies.

The decision to initiate drotrecogin alfa (activated) therapy may be influenced by preexisting conditions that compound the risk for bleeding.¹³ Specific conditions that may influence the analysis of benefit versus risk are listed in TABLE 3 and include concurrent use of heparin, thrombo- cytopenia, INR >3.0, and recent administration of oral anticoagulants, antiplatelet drugs, aspirin, or thrombolytic therapy. Specific contraindications to drotrecogin alfa (activated) therapy are listed in TABLE 3 and include conditions such as active internal hemorrhage, recent hemorrhagic stroke, or recent head trauma, which predispose the patient to serious, life-threatening bleeding. If a patient requires a procedure, such as surgery, that may involve bleeding, the manufacturer recommends that drotrecogin alfa (activated) infusion be discontinued for at least 2 hours before the procedure.¹³

Dosage, Administration, and Monitoring: The recommended dosage for drotrecogin alfa (activated) is 24 mcg/kg/hr for 96 hours by intravenous infusion through a dedicated peripheral intravenous line or through a dedicated lumen of a central venous catheter.^11,13 Dosage adjustments are not recommended, particularly in light of the finding that there are no clinically relevant differences in the pharmacokinetics of drotrecogin alfa (activated) secondary to age, gender, renal insufficiency, or hepatic dysfunction.^11,13 Detailed guidelines for the preparation and administration of drotrecogin alfa (activated) are summarized in the prescribing information.¹³

There are no specific laboratory tests or markers for monitoring drotrecogin alfa (activated) therapy. As established by the PROWESS trial, monitoring of plasma protein C levels is not useful given that therapeutic benefits were achieved regardless of protein C status.¹¹ Since coagulopathies related to severe sepsis and drotrecogin alfa (activated) treatment can prolong the activated partial thromboplastin time (APTT), the APTT is not recommended for the evaluation of coagulation status during treatment.¹³ The prothrombin time (PT) is better suited for monitoring coagulopathies in the severe sepsis patient undergoing drotrecogin alfa (activated) treatment because drotrecogin alfa (activated) has no appreciable effect on this parameter.¹³

Role of the Pharmacist in the Management of Severe Sepsis
Given the complexity of the pathophysiology and clinical manifestations of severe sepsis, there is ample opportunity for the pharmacist to contribute to the care of the septic patient. Since an infectious process is the major precipitating factor for sepsis in the critically ill patient, pharmacists will likely participate in the development of appropriate antimicrobial strategies. In many cases, the pharmacist will be called upon to participate in the selection and monitoring of antimicrobial regimens, including making dosage adjustments based on renal or hepatic function.

As sepsis progresses to severe sepsis with accompanying hypotension, organ hypoperfusion, and organ dysfunction, pharmacists will be involved with pharmacotherapy approaches to manage hemodynamic complications of severe sepsis. Based on the ability of drotrecogin alfa (activated) to significantly reduce mortality in severe sepsis patients, physicians are highly likely to consider the use of drotrecogin alfa (activated) in many sepsis patients. In addition to dose calculation and preparation of drotrecogin alfa (activated) intravenous solution, the pharmacist can assist in appropriate patient selection based on knowledge of clinical trial data, adverse effects, warnings, and contraindications, particularly in regard to the potential complication of bleeding.

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Table 3: Warnings and Contraindications Concerning Drotrecogin alfa (activated)

Warnings (conditions that may increase risk of bleeding with drotrecogin alfa [activated] therapy) ?Concurrent heparin therapy ?Thrombocytopenia ?INR >3.0 ?Evidence of recent gastrointestinal bleeding ?Thrombolytic therapy within past 3 days ?Administration of oral anticoagulants, glycoprotein IIb/IIIa inhibitors, aspirin >650 mg/day, or other antiplatelet drugs within past 7 days ?History of ischemic stroke within past 3 months ?Evidence of intracranial aneurysm or arteriovenous malformation ?Known bleeding diathesis (any state that predisposes to bleeding), any condition in which bleeding is a significant hazard, or any situation where the location of hemorrhage makes it difficult to manage ?Chronic severe hepatic disease

Contraindications (conditions in which bleeding could be associated with a high risk of death or severe morbidity) ?Evidence of active internal bleeding ?Hemorrhagic stroke within past 3 months ?Severe head trauma, intracranial surgery, or intraspinal surgery within past 2 months ?Trauma with an increased risk of life-threatening bleeding ?Presence of an epidural catheter ?Presence of an intracranial neoplasm, mass, or evidence of cerebral herniation

1. American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference: definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med 1992;20:864-74. 2. Anderson RN. Deaths: Leading causes for 1999. National vital statistics reports; vol 49 no 11. Hyattsville, Maryland: National Center for Health Statistics. 2001. 3. Angus DC, Linde-Zwirble WT, Lidicker J, et al. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med 2001;29:1303-10. 4. Fish DN. Optimal antimicrobial therapy for sepsis. Am J Health-Syst Pharm 2002;59(suppl 1):S13-19. 5. Bone RC, Grodzin CJ, Balk RA. Sepsis: a new hypothesis for pathogenesis of the disease process. Chest 1997;112:235-43. 6. Rangel-Frausto MS, Pittet D, Costigan M, et al. The natural history of the systemic inflammatory response syndrome (SIRS): a prospective study. JAMA 1995;272:117-23. 7. 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. 8. Kuhl DA. Current strategies for managing the patient with sepsis. Am J Health-Syst Pharm 2002;59(suppl 1):S9-13. 9. Esmon CT. Inflammation and thrombosis: mutual regulation by protein C. Immunologist 1998;6:84-9. 10. Grey ST, Tsuchida A, Hau H, et al. Selective inhibitory effects of the anticoagulant activated protein C on the responses of human mononuclear phagocytes to LPS, IFN-gamma, or phorbol ester. J Immunol 1994;153:3664-72. 11. Bernard GR, Vincent J, Laterre P, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001;344:699-709. 12. Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: a severity of disease classification system. Crit Care Med 1985;13:818-29. 13. Drotrecogin alfa (activated) (Xigris), Eli Lilly and Company, 2001 (prescribing information).