Surviving Severe Sepsis

Severe sepsis is one of the most significant concerns in the treatment of critical care patients, with more than 750 000 cases occurring annually.1 The condition spreads quickly, is often difficult to recognize, and has a mortality rate of 28% to 50%.2–7 Identification of patients at high risk for progressing to severe sepsis is critical and, in many cases, monitoring patients, rather than evaluating for treatment, can increase the risk of mortality.The financial implications of severe sepsis are substantial. Severe sepsis costs an average of $22000 per patient, with a total cost to US hospitals of $16.7 billion.1 The cost of treating a patient in the ICU with severe sepsis is 6 times greater than the cost of treating a patient in the ICU who does not have sepsis.8The role of nurses in preventing the spread of severe sepsis is crucial, because they are in the position to identify patients at the first sign of becoming septic. Recognizing the signs that a patient has sepsis or has risk factors for developing sepsis allows appropriate treatment to begin early in the course of the condition. The sooner that treatment of sepsis begins, the less likely that it will spread to involve the patient’s organs and start a life-threatening cascade of events.In October 2002, Phase I of the Surviving Sepsis Campaign was initiated to increase education regarding this condition and to establish guidelines to dictate appropriate early treatment of patients at risk for progressing to severe sepsis.9 In progressing to Phase II, 11 international healthcare associations gathered in 2003 to develop a consensus opinion on steps that should be taken in the ICU when treating patients with severe sepsis in order to reduce overall mortality.10Although these guidelines offer hope of reducing mortality caused by sepsis, the optimal course of action is prevention. Hand disinfection, early removal of invasive tubes and catheters, 30° head elevation for patients on mechanical ventilation, early enteral nutrition, and adherence to the CDC Guidelines for avoiding antibiotic resistance11 can limit the opportunity for infections that can lead to sepsis.Recognizing the risk of developing severe sepsis requires an understanding of the body’s systemic response to infection (Figure 1). During a normal response, when an antigen enters the bloodstream, the immune system releases proinflammatory mediators, including TNF-α (tumor necrosis factor), IL-1b (interleukin), chemokines, prostaglandins, and platelet-activating factor, to clear the antigen and promote recovery of affected tissue. The coagulation cascade is initiated, converting fibrinogen to fibrin, leading to the development of a clot to isolate the antigen. To maintain this clot, plasminogen activator inhibitor-1 and thrombin activatable fibrinolysis inhibitor are released to suppress fibrinolysis, which is necessary to allow the time needed to destroy the antigen before the body lyses the clot.With the antigen isolated, the proinflammatory mediators attract activated neutrophils, which engulf the antigen. To prevent the proinflammatory response from damaging normal tissues, anti-inflammatory mediators are released, including IL-4 and TGF-β (transforming growth factor). The balance of inflammatory and anti-inflammatory mediators restricts the inflammatory response to the local site of the infection.When sepsis occurs, this balance is upset and the immune response is not localized to the area around the antigen, but becomes systemic. The excess coagulation, exaggerated inflammation, and impaired fibrinolysis associated with the immune response quickly spread beyond the infected area. The imbalance of the immune response favors coagulation, with increased generation of thrombin and deposition of fibrin. These fibrin clots lead to microvascular hypoperfusion, diminished oxygen delivery, and tissue necrosis. Organ failure follows and the condition progresses to severe sepsis. The procoagulant state results in further endothelial damage, while the vascular damage caused by coagulation leads to the release of more neutrophils and inflammatory cytokines.This self-perpetuating chain of events results in decreased blood flow to organ tissue. Cardiac output may remain normal or even increase but, at the capillary level, tissue perfusion is impeded and oxygenation is impaired. Tissue oxygenation is a critical indicator of sepsis that can be detected before organ failure occurs. An effective means of assessing tissue oxygenation is to measure the oxygen saturation of central venous or mixed venous blood (Svo2), which reflects the amount of oxygen left in the blood after completing circulation. Normal Svo2 saturation is approximately 60% to 75%, with the remaining 25% to 40% having been extracted during circulation.12 Generally in severe sepsis, clotting will obstruct microcapillary perfusion, causing increases in Svo2 levels. In some cases, blood flow is decreased, and the tissue will extract a higher percentage of available oxygen, reducing Svo2 levels. Therefore, in severe sepsis, any variation from normal Svo2 levels should be viewed as consistent with severe sepsis.The causes of sepsis are not fully understood, making treatment difficult. Factors associated with increased risk of developing sepsis include trauma to the gastrointestinal tract, perforation of the small intestine, surgery, chronic debilitating conditions such as diabetes, use of invasive procedures and devices in the ICU setting, and treatment with immunosuppressant drugs.13Early identification of severe sepsis is crucial, as the patient’s risk of mortality increases rapidly if the condition spreads to involve multiple organs (Figure 2).1,14 Sepsis-associated mortality following the failure of 1 organ is approximately 20%. When 2 organs fail, the rate of mortality is approximately 40%. The mortality rate when 3 organs fail is 65% to 70% and 75% to 85% when 4 or more organs fail.Currently, recognizing patients at risk for developing sepsis is difficult due to limited identifying signs and symptoms. However, researchers are assessing biomarkers that will indicate patients at risk, similar to using troponin to identify patients at risk for a myocardial infarction. Protein C levels have been identified as a potential indicator for the development of sepsis.15 Until these biomarkers have been established, physical guidelines are used to identify patients at risk.Keys to identifying a patient with severe sepsis:Other important indications of organ dysfunction include altered consciousness, tachypnea, tachycardia, urine output of less than 0.5 mL/kg/hour, platelet count less than 80 000/mm3 or a 50% decrease in platelets over 3 days, and unexplained metabolic acidosis (Figure 3).17The goals of sepsis treatment are to manage the infection and the body’s response to the infection. Preventing sepsis is always the best option. However, once an infection is present, treatment must be prompt. Empiric antibiotic therapy should be instituted to control the original source of the infection (with blood cultures guiding treatment whenever possible). However, once severe sepsis has begun, treatment options are limited. In order to standardize treatment options, the Surviving Sepsis Campaign provided several evidence-based treatments for severe sepsis. The goal of providing these guidelines is to standardize the treatment of severe sepsis and generate an improved outcome.The Surviving Sepsis Campaign is a worldwide project with the goal of decreasing mortality due to sepsis by 25% in the next 5 years. It reflects the commitment and deliberation of critical care experts from 11 international organizations. After more than a year of systematic review and study, 45 recommendations for care were announced and officially implemented in February 2004 at the Society of Critical Care Medicine Congress.18 The guidelines are to be regularly reviewed and updated at least annually based on cutting-edge research.Many of the Surviving Sepsis Campaign’s suggestions relate to reasonable and prudent care of any critically ill patient, not just those with sepsis. For example, there is guidance for prophylaxis of venous thromboembolism and stress ulcers, along with directives related to the use of sedatives, paralytics, and renal replacement therapy.The Surviving Sepsis Campaign evaluated the available scientific data regarding severe sepsis from level I, large randomized trials, to level V, case studies, uncontrolled studies, and expert opinion (Table 2). The campaign used these designations to rank the currently available treatments for sepsis based on the quality of the science supporting their use. Grade A treatments have the best evidence to support their use, whereas grade E modalities are based on weaker levels of evidence (Table 3).In terms of treating severe sepsis, currently there is no grade A treatment. However, there are 2 grade B treatments:There were 2 grade C treatments, i.e., replacement dose steroid therapy and fluid therapy. There is 1 grade D treatment, i.e., tight glucose regulation and 2 grade E treatments, i.e., vasopressors and inotropes.Although a few grade A-designated sanctions are included in the guidelines, most of the suggestions relate to avoiding what has been proven not to work in sepsis or general critical care strategies, such as ventilator weaning. More than half the 45 recommendations in the Campaign are based on nonrandomized studies, case studies, or expert opinion, reflecting our limited knowledge in managing the septic patient.Making the public aware of the Surviving Sepsis Campaign guidelines will contribute to the goal of decreasing mortality by helping people recognize warning signs of sepsis. Similar efforts have been successful in educating individuals regarding the signs of a heart attack or a “brain attack.” If the public can be taught about early recognition of a “sepsis attack,” they may be able to seek and receive care before it is too late.A review of the suggested treatments will help clarify the Surviving Sepsis Campaign guidelines.Goal-Directed Therapy – Because the unchecked coagulation cascade leads to tissue hypoxia, one treatment that has been attempted is early goal-directed therapy to optimize cardiac output.19 Infusions of colloid or crystalloid, vasoactive agents, and transfusions of red blood cells are used to increase oxygen delivery, with the goal of normalizing Svo2, lactate concentration, base deficit, and pH. In one trial, patients on early goal-directed therapy received more fluid, inotropic support, and blood transfusions during the first 6 hours than the control group, who received standard fluid therapy. During the first 72 hours of treatment, patients receiving the goal-directed therapy had a higher central venous oxygen concentration, lower lactate concentration, lower base deficit, and higher pH than the control group. Mortality was also lower in the aggressive treatment group (30.5%) than in the control group (46.5%).19Recombinant Human Activated Protein C (rhAPC) – rhAPC is the human recombinant form of endogenous activated protein C, a naturally occurring protein that modulates the coagulation cascade.20 Endogenous activated protein C may inhibit plasminogen activator inhibitor (PAI-1), which prevents tissue-type plasminogen activator (t-PA) from binding to fibrin. By facilitating t-PA activity, activated protein C promotes fibrinolysis. Activated protein C inhibits the development of clots that form unnecessarily and reduces the effect of the body’s inflammatory mediators, including neutrophils. Based on its ability to inhibit cytokine release by activated monocytes, activated protein C also may have anti-inflammatory properties (Figure 4).In severe sepsis, protein C levels are significantly depleted. Administration of rhAPC restores balance to the systemic irregularities that occur during sepsis and allows a return to homeostasis in the microvasculature. In the Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial, Xigris reduced the rate of mortality in patients with severe sepsis by 6%, while reducing the mortality rate for those at high risk of death by 13%.21Food and Drug Administration (FDA) guidelines for Xigris indicate use for patients at high risk for death, such as patients having an Acute Physiology and Chronic Health Evaluation (APACHE) II score of 25 or greater (25% chance of mortality), current use of vasopressors (32% chance of mortality), or failure or dysfunction of 2 organs (greater than 40% chance of mortality). In addition, the Extended Evaluation of Recombinant Human Activated Protein C (ENHANCE) trial showed early use of Xigris considerably shortened time in the ICU for patients with severe sepsis.22However, many hospitals have been slow to utilize Xigris as an early treatment. Two primary issues are related to the slow use of Xigris: the potential risk of bleeding and cost of the drug.Overall, the risk of death from bleeding among patients receiving Xigris was low, i.e., 0.5% in the PROWESS trial.23 Serious bleeding events occurred in 3.5% of patients who received Xigris and 2.0% of patients receiving placebo. The majority of patients who experienced bleeding were predisposed to bleeding as a result of conditions including trauma, gastrointestinal tract ulceration or severe coagulopathies. The rate of intracranial hemorrhage was 0.2% in patients receiving Xigris and 0.1% in patients receiving placebo. Among the 850 patients who received Xigris, there were 4 deaths, compared to 2 deaths in the placebo arm. No thrombotic strokes occurred among patients who received Xigris compared to 5 in the patients who received placebo. The potential bleeding risk of Xigris (rhAPC) is low compared to the risk of death from sepsis.The FDA contraindications are for patients who are actively bleeding or have a condition that carries a high risk of death from bleeding, such as recent hemorrhagic stroke or head trauma. In cases where there is concern of bleeding or if the patient must undergo surgery, Xigris can be stopped and, within 30 minutes, 80% of the medication will pass out of the system. Within 2 hours, the drug is completely cleared.In terms of cost, a 96-hour infusion of Xigris in a 70-kg patient costs approximately $6800. Recently published studies suggest that this cost is offset by the cost savings in removing patients from the ICU more rapidly.22,24The ENHANCE trial examined 2378 patients who received Xigris. Patients who received Xigris in the first 24 hours of diagnosis of severe sepsis had a mortality rate of 33%, compared to a mortality rate of 41% in patients who were treated after 24 hours (Figure 5).22 Patients who received Xigris in the first 24 hours spent 4 fewer days in the ICU and spent 3 fewer days on mechanical ventilation (Figure 6). Daily costs associated with ICU stays range between $1000 and $3000,24 so a 4-day stay in the ICU costs between $4000 and $12 000. Cost may be a greater concern if treatment is started later in the course of severe sepsis, but early treatment with Xigris may offset the overall cost.Fluid Therapy – Fluid therapy is most effective early in the course of severe sepsis because, as the condition worsens, there is greater dysfunction at the cellular level. Excess coagulation and impaired fibrinolysis lead to disruption of the endothelial wall, which makes capillaries more permeable. Once severe sepsis is present, the potential for fluid therapy to help starts to diminish. Fluid can leak from the capillaries as fast as it is administered. In addition, severe sepsis often presents with high blood flow states. The problem is not a lack of fluid, but of maldistribution of blood flow due to microcapillary obstruction. When fluid is given, an oxygen end point (e.g., Svo2) helps determine when fluid therapy is beneficial.Replacement Dose Steroids – Adrenal insufficiency occurs in between 25% and 40% of patients with septic shock and is indicated by the need for vasopressors.25–27 Appropriate dosing of steroids provides support to dysfunctional adrenal glands and enhances vasomotor tone. Physiologic doses of intravenous steroids (200 to 300 mg/day for 7 days) in patients with relative adrenal insufficiency who were in septic shock achieved significant shock attenuation and mortality reduction.28 Earlier studies from the 1980s tested doses greater than 300 mg/day and showed that steroids were not only ineffective, but also potentially detrimental in sepsis treatment.29–31 It is not clear how to best diagnose adrenal insufficiency, e.g., total cortisol levels, adrenocorticotropic hormone (ACTH) testing. However, replacement dose steroid treatment for patients who require vasopressors is a logical step at this time.Intensive Insulin Therapy – Insulin therapy to maintain blood glucose levels at 80 to 110 mg/dL has also been shown to reduce morbidity and mortality among critically ill patients undergoing surgery, compared to conventional therapy that maintained blood glucose at 180 to 200 mg/dL.32 Intensive insulin therapy reduced the incidence of septic episodes by 46% and decreased mortality (12.5%) among patients with bacteremia compared to patients who received conventional therapy (29.5%).Vasopressor Therapy – The goal of vasopressor therapy is to increase vascular constriction, leading to improved perfusion. However, failure of the capillaries and poor oxygen delivery to the cells are not resolved by this treatment. In severe sepsis studies the need for vasopressors was associated with a high risk of mortality (Figure 7).23 In the placebo group, the mortality rate of patients who did not receive a vasopressor was 20%. In patients who received a low-dose vasopressor, the mortality rate was 37%, and in patients who received high-dose vasopressors, the mortality rate was 58%. Use of escalating doses of vasopressors may be a proxy for increases in the severity of the sepsis. Therefore, increased use of vasopressors should be an indicator that severe sepsis is worsening.The campaign’s guidelines made no attempt to prioritize or formulate a hierarchy of interventions. To make a cumbersome list of endorsements more clinically applicable, a “bundling” system has been proposed by the Institute of Healthcare Improvement to encourage change in practice.72 It is important to note that these bundled interventions have not been for or are a for the guidelines in a were 4 4 hours and 24 hours and 4 hours and 24 hours with Recently the recommendations have been to and hours that in the case of sepsis, a in treatment significantly increases risk of are and must be before results are when results are antibiotic therapy can be also that can be The of an lactate level the disruption and cellular of sepsis. It also a need for fluid 6 hours with shock hours on by on the of glucose control in patients, as as multiple studies supporting for patients with a of sepsis. In addition, and are for and organ perfusion hours with to the support of septic and the multiple mediators in sepsis lead to inflammation, causing to vascular the The and leading to and of this can be for the a vascular the of fluid to make no in so or may be The remaining recommendations in this are based on the Therapy trial, which with the of septic patients with or In to blood and output guidelines, the successful end for included a higher than central venous and the of central venous oxygen saturation as a of overall oxygen suggestions for inotropic support and blood must be early in sepsis before cells to and organ are included for the treatment of but critical care must that there is a between to and blood or may be appropriate vasopressors for sepsis, but low-dose for renal should not be may be for patients not to conventional vasopressors, but it should not be increased beyond an of low-dose steroids than the high-dose therapy of the for patients vasopressor steroids at 200 to 300 mg/day for 7 days, evaluated by shock and reduced mortality in patients with relative adrenal the use of steroids is and this is only a grade C hours with with severe sepsis and septic shock are among the most critically ill in the Once the of and coagulation begins, it is difficult to and nurses are left to a patient’s organ failure and Critical care nurses a role in preventing sepsis and severe sepsis by identifying patients at risk early in the development of the which can significantly increase of cases where severe sepsis occurs, the Surviving Sepsis Campaign hope for a and to patient Critical care nurses must with the guidelines and as change in for their