Recognizing and managing severe sepsis: a common and deadly threat.

Abstract: Through a literature review, the epidemiology and pathophysiology, including alterations in inflammation, coagulation, and impaired fibrinolysis that occur in the course of severe sepsis, is presented. Treatment guidelines that are evidence-based and endorsed by 11 professional societies representing multispecialty groups are described. Severe sepsis is common; 750,000 cases are estimated to occur annually in the United States. The mortality rate for severe sepsis still ranges from 30 to 50%, and is as high as 80 to 90% for septic shock and multiple organ dysfunction. Severe sepsis exists along a continuum initiated by a localized infection that triggers a systemic response. A cascade of inflammation and activation of the coagulation system associated with impaired fibrinolysis leads to alterations in microvascular circulation associated with organ dysfunction, severe sepsis, multiple organ dysfunction syndrome, and death. In an attempt to improve care and reduce mortality, the Surviving Sepsis Campaign and The Institute for Healthcare Improvement (IHI) have created two sepsis treatment bundles.

Key Words: severe sepsis, treatment guidelines, ICU 

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If you could reduce the mortality rate by one quarter in a patient population afflicted with a condition with mortality rates of 30 to 50%, and which affects 750,000 people annually in the US, would you? The condition is severe sepsis. Evidence-based guidelines and tools are available now that can help you achieve reductions in mortality and reduce length of stay. The Surviving Sepsis Campaign is the result of a collaborative effort between the Society of Critical Care Medicine, the European Society of Intensive Care Medicine, and the International Sepsis Forum, and has the support of 11 international organizations. The overall goal is to achieve a 25% reduction in sepsis mortality by the year 2009. (1)

Severe Sepsis: What Is It, Really?

Severe sepsis exists along a continuum initiated by a localized infection that triggers a systemic response, called systemic inflammatory response syndrome (SIRS) (Fig. 1). Sepsis is simply the combination of suspected or proven infection and the presence of at least two SIRS signs. Severe sepsis is defined as acute organ system dysfunction associated with infection.

Septic shock, a subgroup of severe sepsis, has been defined as "sepsis-induced hypotension (systolic blood pressure [less than or equal to]90 mm Hg or a reduction of [greater than or equal to]40 mm Hg from baseline) despite adequate fluid resuscitation along with the presence of perfusion abnormalities that may include, but are not limited to, lactic acidosis, oliguria, or an acute alteration in mental status. Patients who are receiving inotropic or vasopressor agents may have a normalized blood pressure at the time that perfusion abnormalities are identified." (2)

A detailed breakdown of the definitions of organ dysfunction referred to by Bernard et al (3) and associated with severe sepsis include shock, as well as specific markers of organ dysfunction: renal--urine output of less than 0.5 mL/kg/h persisting after fluid resuscitation; respiratory--a Pa[O.sub.2]/Fi[o.sub.2] result of less than 250; hematologic--platelet count less than 80,000/[mm.sup.3] or a decrease of more than 50% in 72 hours; metabolic acidosis--combination of pH [less than or equal to]7.30 or a base deficit [greater than or equal to]5 mmol/L associated with a serum lactate level greater than 1.5 times the upper limit of normal; or shock and cardiovascular--systolic blood pressure less than 90 mm Hg or requiring the use of a vasopressor to maintain blood pressure.

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Angus completed an evaluation of discharge data from seven states that, when extrapolated, suggests that more than 750,000 episodes of severe sepsis occur each year in the United States, (4) resulting in the tenth most common cause of death. (5) With an estimated mortality of more than 220,000 persons per year in the US, (4) sepsis exceeds the annual US mortality for patients with acquired immune deficiency syndrome, (5) breast cancer, (6) colon cancer (7) or myocardial infarction. (8) Angus also found that sepsis represents 2 to 3% of all hospital admissions. Another inquiry found that sepsis accounted for 2.0% of all hospitalizations and that 59% of patients with sepsis require intensive care unit (ICU) care, composing 10.4% of ICU admissions. (9) Despite the technological advances over the last 2 decades, more potent antimicrobial therapy and improved support of the critically ill, the mortality rate for severe sepsis still ranges from 30 to 50%, and may be as high as 80 to 90% for septic shock and multiple organ dysfunction. (3,10-13)

Presenting Symptoms

In clinical trials, patients present with similar patterns of infection and initial organ dysfunction. Respiratory system dysfunction is the most common presenting symptom, followed by shock and renal system dysfunction. The most common site of infection is the lung, followed by intra-abdominal and urological sources. The presence of infection can be determined by positive culture data, or based on the clinical picture. In 22 to 33% of patients enrolled in sepsis clinical trials, culture results were never positive for a pathogen. When culture results from patients with severe sepsis are positive, bacteria are most commonly identified. (14-16) Gram negative bacteria are identified in 22 to 37% of all positive cultures, while Gram positive bacteria are identified in 25 to 50% of positive cultures. (14-16)

Clinically, pneumonia is the most common trigger for severe sepsis, followed by peritonitis (often resulting from bowel perforation) and urinary tract infection with or without pyelonephritis. (14-16) Although the aforementioned are the most common, infections of the central nervous system, skin and soft tissue, primary blood stream infection, joints, and infected artificial devices can also trigger the physiologic responses that result in organ system dysfunction and severe sepsis.

The presence of SIRS and the progression of sepsis to severe sepsis is common. Rangel-Frausto et al (17) measured the incidence and progression of SIRS to sepsis and severe sepsis in three general wards and three intensive care units. Of the 3,708 patients evaluated, 2,521 (68%) developed at least two SIRS criteria. Among the group with SIRS, 26% developed sepsis, 18% developed severe sepsis, and 4% developed septic shock.

Mechanism of Disease

Regardless of the infecting organism, clinical presentation, or combination of acute organ dysfunctions, sepsis-associated physiologic changes share a common set of derangements. A cascade of inflammation and activation of the coagulation system associated with impaired fibrinolysis leads to alterations in microvascular circulation associated with organ dysfunction, severe sepsis, multiple organ dysfunction syndrome, and death. (18,19) The cascade begins when, in response to infection, the innate immune system is activated through recognition of foreign substances, such as bacterial lipopolysaccharide (endotoxin or LPS). (20) Other triggers include bacterial cell wall components: peptidoglycan, lipoproteins and bacterial DNA. (21) Macrophages begin to secrete inflammatory cytokines in response to intracellular signaling through toll-like receptors (22) and membrane-anchored proteins, such as CD 14. (23) Inflammatory mediators, tumor necrosis factor-alfa (TNF-a), interleukin-1 (IL-1), interleukin-6 (IL-6) and interferon-gamma (INF-gamma) have all been identified as originating from activated macrophages. (24) Neutrophils become activated in response to infection. Through L-selectin on the neutrophil binding with E- and P-selectin on endothelial cells, neutrophil rolling and adhesion to the endothelium begins. (25)

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Tissue factor is initially released through cytokine-induced tissue factor expression on monocytes and certain subsets of endothelial cells. (20,26,27) The coagulation cascade then continues as tissue factor reacts with factor Vila, ultimately leading to thrombin generation. Thrombin (factor IIa) is a major activator of platelets and acts through protease-activated receptors 1 and 4 on the endothelium producing proinflammatory cellular responses. (28,29)

The end result is the development of a proinflammatory and procoagulant state that results in abnormalities in the microvascular circulation, including cessation of flow through capillaries. (30)

In the setting of severe sepsis, fibrinolysis is also impaired. Plasmin is the enzyme primarily responsible for dissolving the fibrin clot. Endothelial cells are the principal source of t-PA. (31) Both TNF-[alpha] and IL-1 increase plasminogen activator inhibitor-1 (PAI-1) synthesis or release from endothelial cells and also decrease plasminogen activator synthesis. (32) PAI-1 is produced in endothelial cells and complexes with t-PA and inhibits the ability of t-PA to activate plasminogen. (33) The end result is a reduced ability to break down the microvascular thrombin clots that form as a result of the procoagulant state of sepsis.

Endothelial Dysfunction and Impaired Microcirculation in Sepsis

The endothelium is the largest single organ in the body with a surface area of 4000 to 7000 [m.sup.2]. During a normal physiologic state, the endothelium regulates vasomotor tone, maintains an anticoagulant state, and regulates the transmigration of leukocytes into the surrounding tissues. (34)

In patients with sepsis, the endothelium becomes damaged as inflammation and endothelial cell activation ensues. (35) The pro-coagulant response described previously leads to thrombin generation and the expression of adhesion molecules on endothelial cells, eg, I-CAM, E-selectin, monocyte-chemoattractant protein-1, which attract and loosely bind neutrophils to the surface of the endothelial cell. (36) As the neutrophils are bound and released by these adhesion molecules, they appear to roll along the surface of the endothelium. Release of proteolytic enzymes, eg, elastase and myeloperoxidase, and reactive oxygen species such as peroxidases, superoxide dismutase and nitric oxide synthase from neutrophils, damage the endothelial cells.

Injury caused by proteolytic enzymes involves the cytoskeletal structure resulting in a loss of the intact junction between endothelial cells (Fig. 2). Loss of an intact endothelial barrier allows for the relaxation of vascular smooth muscle via action of endothelin-1 and nitric oxide with a subsequent leak of plasma and transmigration of neutrophils into the interstitial space. Damage to the endothelial cells can be demonstrated by increases in circulating levels of thrombomodulin, ICAM-1, E-selectin and von Willebrand factor. (37) Mutunga et al demonstrated increased plasma levels of endothelial cells in humans with septic shock, implying an increase in endothelial shedding as injury progresses. (38) Loss of endothelial cell integrity with subsequent loss of plasma to the interstitial space manifests clinically as a distributive shock resulting in alterations in microcirculatory flow.

The microcirculation is the vast network of small and large end-organ capillaries, which perfuse all tissue beds. Multiple mechanisms, including endothelial cell activation, contribute to the impairment in microcirculatory perfusion in patients with severe sepsis (Fig. 3). (4,39,40)

Decreased capillary perfusion in patients with severe sepsis results in impaired oxygen delivery to the tissues. Despite normalization of blood pressure, cardiac index and other hemodynamic variables in patients with severe sepsis, alterations in microcirculation persist. (41,42) Microvascular alterations do predict outcome in patients with severe sepsis. Sakr et al (42) recently studied sublingual microcirculatory perfusion in resuscitated patients with septic shock using an orthogonal polarization spectral imaging technique. Both survivors and nonsurvivors had decreased capillary perfusion at the onset of septic shock, despite normalizations of hemodynamic variables with the use of fluids and vasopressor. Over the course of their ICU stay, a significant increase in capillary perfusion was observed in patients who survived, compared with those who died as a result of shock or their persistent organ failure. (42) Therefore, as assessment of microcirculatory alterations continues to be developed and validated for use at the bedside, new tools may become available to assess response to therapeutic interventions.

Clinical Manifestations of Sepsis

Individually, many of the previously described departures from normal physiology may not be apparent in the physical examination or while reviewing the clinical data commonly available today. However, when presented with a patient who is suspected of having an infection of any source and who has the physiologic changes of systemic inflammation, activation of the coagulation cascade, impaired fibrinolysis, and altered microcirculation, the astute clinician can detect the ravages of severe sepsis by the development of organ system dysfunction.

Such findings manifest themselves daily in hospitalized patients throughout the country. Any new findings, such as those shown in Figure 4, occurring in the presence of infection are each indicators of alterations in tissue perfusion manifesting as clinical signs and symptoms of severe sepsis. (11,43,44) While only one organ system dysfunction is required in the definition of severe sepsis, one does not need to spend much time in the ICU to recognize that multiple organ dysfunction often ensues in patients with sepsis. Mortality from sepsis increases as the number of dysfunctional organs increases (12,43,45-47) (Fig. 5).

Treatment Recommendations

The Surviving Sepsis Campaign (SSC) completed a systematic review of the evidence available for therapies commonly applied to treat severe sepsis and septic shock. (1) Table 1 displays most of the therapies and the grade assigned by the SSC. The publication of the guidelines completed phase 2 of the Surviving Sepsis Campaign, allowing for implementation, or phase 3 to begin. The Surviving Sepsis Campaign partnered with the Institute for Healthcare Improvement (IHI) to translate the published guidelines into a more practical set of protocols that could be used at the bedside. Quality measures, as well as tools for evaluating the quality measures, have also been developed.

The Institute for Healthcare Improvement (48) has identified sepsis as an area of focus and has subsequently identified several deficiencies that lead to suboptimal care of patients with severe sepsis:

1. Inconsistency in the early diagnosis of severe sepsis and septic shock.

2. Frequent inadequate volume resuscitation without defined endpoints.

3. Late or inadequate use of antibiotics.

4. Frequent failure to support the cardiac output when depressed.

5. Frequent failure to control hyperglycemia adequately.

6. Frequent failure to use low tidal volumes and pressures in acute lung injury.

7. Frequent failure to treat adrenal inadequacy in refractory shock.

To address these deficiencies, the Surviving Sepsis Campaign and IHI have built upon the Surviving Sepsis Guidelines and have created two sepsis treatment bundles to guide therapy. The premise is that by distilling the Surviving Sepsis Guidelines into two sets of interventions (bundles), change will occur and lives will be saved. (49) The Sepsis Resuscitation Bundle (Table 2) contains 5 items that should be instituted as soon as possible, but certainly within the first 6 hours after the patient presents for medical care. The Sepsis Management Bundle (Table 3) contains 4 items that should be accomplished as soon as possible, but certainly within the first 24 hours of sepsis care. Implicit in the use of the bundles is the need to adopt all the elements contained in the bundle. One cannot choose to apply only selected items from the bundle and expect to achieve comparable benefit. The IHI sepsis website also provides tools to screen patients for severe sepsis, as well as to measure success with adherence to implementing the bundles (http://www.ihi.org/IHI/Topics/CriticalCare/Sepsis/).

Timely recognition and diagnosis of severe sepsis is the first step. Applying the evidence-based guidelines (Table 1) created under the auspices of the Surviving Sepsis Campaign is the second step. (1) Following up by measuring adherence to the guidelines is equally important to successfully implement change. (49) There have been published findings of reduced mortality associated with implementation of the sepsis bundles. Gao reported that patients whose care was compliant with the Sepsis Resuscitation Bundle benefited with a 26% (n = 101, P = 0.045) reduction in hospital mortality compared with those patients whose care was not compliant with this bundle. (50) Other studies have examined the impact of protocol-driven care for patients with severe sepsis. (51,52) Although these studies did not utilize the IHI bundles, reductions in 28-day mortality of 18% (n = 120, P = 0.040) and 12.5% (n = 189, P 0.035), respectively, were observed. A database and supporting data collection worksheets are freely available from the IHI to assist with measuring adherence to the sepsis bundles.

Tools are available for use today that will guide the clinician in providing comprehensive and evidence-based care to the patient suffering from severe sepsis. Making the diagnosis of severe sepsis with or without organ dysfunction in the setting of suspected or proven infection is important. Hopefully, once the patient is identified, multidisciplinary teams will rapidly and appropriately apply a series of evidence-based interventions. If the interventions are applied in a systematic fashion and adherence to standardized guidelines is followed and measured, then we will know if the Surviving Sepsis Campaign's goal of a 25% reduction in mortality from sepsis by the year 2009 had been obtained.

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Will your darkest hour write a blank check on your soul?
--Slaid Cleaves

Douglas Schlichting, RN, MS, MPA, and Jill Shwed McCollam, PharmD, BS, BCPS 

From Eli Lilly and Company, Indianapolis, IN.

Reprint requests to Douglas Schlichting, Lilly Corporate Center, DC 6835, Indianapolis, IN 46285. Email: [e-mail]

Drs. Schlichting and McCollam are employees and shareholders of Eli Lilly and Company. Eli Lilly and Company is the manufacturer of drotrecogin alfa (activated).

Accepted January 25, 2007.

Deficiencies that may lead to suboptimal care of patients with severe sepsis:

1. Inconsistency in the early diagnosis of severe sepsis and septic shock.

2. Frequent inadequate volume resuscitation without defined endpoints.

3. Late or inadequate use of antibiotics.

4. Frequent failure to support the cardiac output when depressed.

5. Frequent failure to adequately control hyperglycemia.

6. Frequent failure to use low tidal volumes and pressures in acute lung injury.

7. Frequent failure to treat adrenal inadequacy in refractory shock.

RELATED ARTICLE: Key Points

* Severe sepsis is common; an estimated 750,000 cases occur annually in the United States.

* The mortality rate for severe sepsis is 30 to 50% and septic shock with multiple organ dysfunction is as high as 80% to 90%.

* A cascade of inflammation and activation of the coagulation system associated with impaired fibrinolysis leads to alterations in microvascular circulation associated with organ dysfunction, severe sepsis, multiple organ dysfunction syndrome, and death.

* The Institute for Healthcare Improvement (IHI) has identified sepsis as an area of focus and identified several deficiencies that lead to suboptimal care of patients with severe sepsis.

* To address these deficiencies, the Surviving Sepsis Campaign and IHI have built upon the Surviving Sepsis Guidelines and created two sepsis treatment bundles to guide therapy for the patient suffering from severe sepsis.

Table 1. Topics addressed by the surviving sepsis campaign

                       Surviving Sepsis Guidelines 2004
                       Grade of Evidence--Selected Interventions
Grade A                Grade B                  Grade C

Vent weaning SBT       Early goal-directed      Low-dose steroids
  protocol               therapy
DVT/PUD prophylaxis    Drotrecogin alfa         Semirecumbent body
                         (activated)              position
No high dose steroids  ALI vent protocol        No bicurbonate
No supraphysiologic    Renal replacement        No evidence support for
  cardiac index          dialysis                 one type of fluid over
                       No renal dose dopamine     another
                         Sedation holiday or
                         protocol Conservative
                         transfusions

Surviving Sepsis Guidelines 2004
Grade of Evidence--Selected Interventions
Grade D               Grade E

Glucose <150mg/dl     Source control
Appropriate cultures  Broad spectrum early antibiotics
  before antibiotics
                      Vasopressors NE, DA
                      Patients requiring pressors should have arterial
                        catheter
                      Guidance around use inotropes
                      Management of thrombocytopenia
                      Consider limiting support

Table 2. Sepsis resuscitation bundle

(To be accomplished as soon as possible and scored over first 6 hours):
  1. Serum lactate measured.
  2. Blood cultures obtained prior to antibiotic administration.
  3. From the time of presentation, broad-spectrum antibiotics
     administered within 3 hours for ED admissions and 1 hour for non-ED
     ICU admissions.
  4. In the event of hypotension and/or lactate >4 mmol/L (36 mg/dL):
     a) Deliver an initial minimum of 20 mL/kg of crystalloid (or
        colloid equivalent).
     b) Apply vasopressors for hypotension not responding to initial
        fluid resuscitation to maintain mean arterial pressure (MAP)
        >= 65 mm Hg.
  5. In the event of persistent hypotension despite fluid resuscitation
     (septic shock) and/or lactate >4 mmol/L (36 mg/dL):
     a) Achieve central venous pressure (CVP) of >= 8 mm Hg.
     b) Achieve central venous oxygen saturation (Scv[O.sub.2]) of
        >= 70% or a mixed venous oxygen saturation (Sv[O.sub.2]) of
        >= 65%.

Table 3. Sepsis management bundle

(To be accomplished as soon as possible and scored over first 24 hours):
  1. Low-dose steroids administered for septic shock in accordance with
     a standardized ICU policy.
  2. Drotrecogin alfa (activated) administered in accordance with a
     standardized ICU policy.
  3. Glucose control maintained at or above the lower limit of normal,
     but <150 mg/dL (8.3 mmol/L).
  4. Inspiratory plateau pressures maintained <30 cm [H.sub.2]O for
     mechanically ventilated patients.