Article, Emergency Medicine

Sepsis in the 21st century: recent definitions and therapeutic advances


Sepsis in the 21st century: recent definitions and therapeutic advances

H. Bryant Nguyen MD, MS*, Dustin Smith MD

Department of Emergency Medicine, Loma Linda University, Loma Linda, CA 92354, USA

Received 23 June 2006; revised 14 August 2006; accepted 29 August 2006

Abstract Sepsis as a disease has received renewed interests since recent publications of a revised clinical definition and crucial clinical trials showing the benefits of early goal-directed resuscitation, recombinant human activated protein C, and low-dose corticosteroids. The epidemiology of sepsis has also been further examined. Management guidelines and international quality improvement efforts have been developed targeting increased disease identification, clinician education, and optimal patient care with the result of decreasing patient mortality. The evidence suggests that early recognition and early intervention are most important in affecting outcome. This article will summarize these developments in the diagnosis and management of sepsis at the turn of this century.

D 2007


Sepsis has been defined as a systemic response to a local infection [1]. However, clinicians often ponder and then skip over this diagnosis when a patient presents to the emergency department (ED) with a productive cough, fever, tachycardia, and a multitude of constitutional symptoms. Therapies for such patients in the ED have primarily consisted of anti- biotics. In addition, fluids have been the mainstay for cardiovascular support, and vasopressors are initiated if the patient becomes hypotensive and unresponsive to fluid resuscitation. When a patient is admitted to the intensive care unit (ICU), he or she is further placed among a group of bcritically ill patients.Q It is not until a few days into the hospital stay when culture results are positive, the patient is receiving multiple vasopressors, multiple antibiotics, and mechanical ventilation that the treating physicians seriously

* Corresponding author.

E-mail address: [email protected] (H.B. Nguyen).

consider the patient bseptic.Q However, we would argue that this patient is now in septic shock with multiorgan failure and with a risk for mortality approaching 80%. The patient was already septic the minute he or she presented at triage.

The problem is that sepsis has been associated with the Systemic Inflammatory Response Syndrome [1], resulting in only 17% of physicians surveyed agreeing to this definition [2]. However, 83% of physicians in the same survey agreed that the sepsis diagnosis is frequently missed. With respect to therapies, many clinical trials examining novel therapies have failed miserably. Agents without therapeutic success included antilipid, interleukin-1-receptor antagonist, platelet activating factor inhibitor, antitumor necrosis factor monoclonal antibody, immunoglobulin, ibuprofen, high-dose corticosteroid, anti-endotoxin, anti- thrombin III, and many others [3]. Thus, it is no surprise that sepsis often becomes a syndrome of last resort rather than a diagnosis until proven otherwise. Even when sepsis is timely recognized, the therapies would not change from what the patient was already receiving, that is, antibiotics, fluids, and vasopressors.

0735-6757/$ – see front matter D 2007 doi:10.1016/j.ajem.2006.08.015

At the turn of the century, starting in 2001, the tide changed for sepsis with the publication of the first successful clinical trial examining a novel therapeutic agent, recombinant human activated protein C (rhAPC) [4]. It became the first Food and Drug Administration-approved agent for severe sepsis therapy, specifically for patients with high risk for mortality. Soon after, other successful clinical trials followed, including therapeutic strategies such as early goal-directed therapy [5], tight glucose control [6], and low-dose replacement corticosteroids [7]. Now, 5 years later, instead of a one-drug-treat-all approach, we have a comprehensive Management strategy that includes a revised sepsis definition [8] and treatment guidelines that involve a Multidisciplinary team approach [9,10]. Most importantly, emergency physicians now play a central role in this changing of the tides [11]. In this article, we will further summarize the chronological development in this century for the management of sepsis.


July 2001

Using the International Classification of Diseases, Ninth Revision, Clinical Modification codes related to infectious process and organ dysfunction, Angus et al [12] examined hospital discharge databases from 7 states and population data from the US Census in 1995. The incidence for severe sepsis was 751,000 cases with 28.6% mortality. The mean age was 63.8 years. Mortality increased with age, from 10% in children to 38.4% in patients older than 85 years. The average length of hospital stay and cost per patient were

19.6 days and $22,100, respectively. The total national cost in the United States for severe sepsis was $16.7 billion. Although there is no definitive data regarding the incidence of sepsis in the ED, we estimate approximately 458,200 cases (or 61% of severe sepsis/septic shock presentations) are first encountered in the ED annually [12,13].

April 2003

The evolution of the pathogens has proceeded as well. From 1979 through 1987, Gram-negative organisms were the main cause of sepsis in the United States, but since that time, Gram-positive organisms have been identified as the most frequent source [14]. Data from Spain published in 2003 found that the most common sources of community- acquired blood stream infections were the lower respiratory tract (20.6%), intra-Abdominal infections (20.1%), and genitourinary tract infections (19.8%), with 43.6% of the pathogens being Gram-positive, most of which were Staphylococcus aureus and Streptococcus pneumoniae [15]. These data support other epidemiological studies suggesting that Gram-positive pathogens have surpassed Gram-negative pathogens as the etiological agents of sepsis [16].


December 2001

To address the overly sensitive definition of sepsis incorporating the SIRS [1,17] and to close the gap between physician knowledge of sepsis and the increasingly available data from clinical trials, the International Sepsis Definitions Conference was held in Washington, DC. The conference was sponsored by the Society of Critical Care Medicine, the European Society of Intensive Care Medicine (ESICM), the American College of Chest Physicians, the American Thoracic Society, and the Surgical Infection Society. The diagnostic criteria for sepsis now include a documented or suspected infection and some of general variables, as well as inflammatory, hemodynamic, organ dysfunction, and tissue perfusion variables [8] (Fig. 1). Infection is a pathologic process caused by the invasion of normally sterile tissue, fluid, or body cavity by pathogenic or potentially pathogenic microorganisms. Severe sepsis refers to sepsis complicated by organ dysfunction. Septic shock is a state of acute circulatory failure characterized by persistent hypotension unexplained by other causes. Hypotension is defined by a systolic blood pressure below 90 mm Hg, a mean arterial pressure (MAP) b60 mm Hg, or a reduction in systolic blood pressure b40 mm Hg from baseline despite adequate volume resuscitation, usually after a 20 to 30 mL/kg crystalloid bolus. Although the consensus conference avoided SIRS as part of the definitions, reflected by 2 of the following: (a) temperature N388C or b368C, (b) heart rate N90 beat/min,

(c) respiratory rate N20 breaths/min, and (d) white blood cell count N12,000 or b4000 cells/mm3 or N10% bands, these variables are still useful for the clinician evaluating the patient with a source of infection at the bedside. For example, if a patient presents with a productive cough, temperature of 38.38C, heart rate of 105 beat/min, respiration of 24 breaths/ min, and the laboratories show a white blood cell count of 13,000 cells/mm3 and chest x-ray with a focal infiltrate, this patient has met the criteria for sepsis in addition to being considered as having pneumonia.

Advances in therapy and the evidence

March 2001 (rhAPC)

The pathogenic mechanism of sepsis involves the activa- tion of both the inflammatory and clotting pathways [19]. There is an initial activation of the clotting cascade by the extrinsic pathway and an attenuation of natural anticoagula- tion responses [19]. Microvascular thrombosis resulting from fibrin formation, inhibited fibrinolysis, and reduced anti- coagulation pathways results in organ perfusion deficits. This cascade leads to multiorgan failure, morbidity, and mortality and is therefore a target for novel therapy. As part of this complex pathway, endogenous activated protein C produc- tion is reduced as a result of down-regulation of thrombo-

Fig. 1 Diagnostic criteria for sepsis, adapted from Levy et al [8]. WBC indicates white blood cell; SBP, systolic blood pressure; Svo2, mixed venous oxygen saturation; INR, international normalized ratio; aPTT, activated partial thromboplastin time. aInfection defined as a pathologic process induced by a microorganism. bSvo2 can be low (b70%) in early sepsis signifying inadequate oxygen delivery and global hypoperfusion. Scvo2 has been used as a surrogate of Svo2 [5,18].

modulin. Activated protein C has anti-inflammatory, antico- agulant, fibrinolytic, and antiapoptotic properties. Thus, the potential benefit of rhAPC (or drotrecogin alfa activated) as a therapeutic agent was studied in a multicenter, international, placebo-controlled clinical trial [4]. A total of 1690 patients with severe sepsis were enrolled, and 28-day mortality was reduced from 30.8% in the placebo group to 24.7% in the treatment group ( P = .005). In subgroup analyses, prespeci- fied in the protocol, rhAPC was found to reduce absolute mortality by 13% in patients with severe sepsis who have an Acute Physiology and Chronic Health Evaluation II [20] scores of z25 or z2 sepsis-induced organ dysfunc- tions [21]. The Food and Drug Administration approved rhAPC for this subgroup of patients with an APACHE II z25. Recent data in patients with single organ dysfunction or an APACHE II score b25 showed that these patients may not be at high risk and will not benefit from rhAPC [22]. As expected, given the anticoagulant properties of rhAPC, the major clinical risk with its use is bleeding. If all bleeding events are considered, administration of rhAPC approximate- ly doubles the risk (3.5% vs 2.0%; P = .06) [21]. The absolute contraindications to the administration of rhAPC are active

internal bleeding; recent hemorrhagic stroke within 3 months; recent intracranial or intraspinal surgery, or severe head trauma within 2 months; trauma with an increased risk of life- threatening bleeding; presence of an epidural catheter; intracranial neoplasm, mass lesion, or evidence of cerebral herniation; or known hypersensitivity to rhAPC.

November 2001 (EGDT)

A trial of early hemodynamic optimization, or EGDT, was conducted in ED patients with severe sepsis or septic shock and revealed a significant mortality reduction [5]. The EGDT is an algorithmic approach to restoration of systemic oxygen delivery through a manipulation of preload (vol- ume), afterload (blood pressure), and contractility (stroke volume) guided by central venous pressure , MAP, and Central venous oxygen saturation (Scvo2) monitoring to preserve effective tissue perfusion within the first 6 hours of disease presentation. Patients were managed by (1) fluid resuscitation with either crystalloid or colloid to achieve a CVP goal of 8 to 12 mm Hg, (2) vasoactive agents to achieve a MAP goal of 65 to 90 mm Hg, (3) blood transfusion to a hematocrit z30%, (4) inotrope therapy, and

(5) intubation, sedation, and paralysis as necessary to achieve a Scvo2 of z70% as measured by continuous central venous monitoring (Fig. 2) [5]. Rivers et al [5] examined efficacy of EGDT in 263 patients with infection associated with hypotension after a fluid bolus and/or serum lactate z4 mmol/L who were randomly assigned to receive standard resuscitation or EGDT in the ED before ICU transfer. During the first 6 hours in the ED, the EGDT group had significantly greater amount of fluid therapy than the

control group (5.0 vs 3.5 L, respectively), red blood cell transfusion (64.1% vs 18.5%, respectively), and inotrope (ie, dobutamine) administration (13.7% vs 0.8%, respec- tively). The primary outcome variable, in-hospital mortality, was 46.5% in the control group versus 30.5% in the EGDT group ( P = .009). Of the patients who survived to hospital discharge, EGDT resulted in a significant 3.8 days shorter hospital length of stay ( P = .04). The EGDT was associated with a significant 2-fold decrease in the incidence of sudden

Fig. 2 Early goal-directed therapy Protocol [5]. Reprinted with permission from Rivers, Nguyen, Havstad, et al: Early Goal- Directed Therapy in Treatment of Severe Sepsis and Septic Shock. N Engl J Med 2001;345:1368-77. Copyright n 2001 Massachusetts Medical Society. All rights reserved. The Institute for Healthcare Improvement recommends a resuscitation bundle incorporating EGDT to be started immediately and completed within 6 hours of recognition of severe sepsis/septic shock [23].

  1. Serum lactate measured.
  2. Blood cultures obtained before antibiotic administration.
  3. From the time of presentation, broad-spectrum antibiotics administered within 3 hours for ED admission.
  4. In the event of hypotension:
    1. Minimum of 20 mL/kg of crystalloid (or colloid equivalent) delivered.
    2. For hypotension not responding to volume resuscitation, vasopressors used to maintain MAP N65 mm Hg.
  5. In the event of persistent arterial hypotension refractory to volume resuscitation (septic shock) and/or initial lactate N4 mmol/L (36 mg/dL):
    1. CVP N8 mm Hg achieved.
    2. Scvo2 N70% achieved.

cardiopulmonary complications, such as cardiac arrest, hypotension, or acute respiratory failure ( P = .02).

August 2002 (Low-dose glucocorticoid therapy)

Glucocorticoids have a fundamental role in a patient’s response to acute stress. However, high levels of inflam- matory cytokines in patients with sepsis can directly inhibit cortisol synthesis [24]. In addition, excessive inflammatory cytokines produced during sepsis can result in systemic or tissue-specific corticosteroid resistance [25,26]. Some patients with septic shock will have inadequate adrenal reserve manifested by an inadequate response when challenged with adrenocorticotropic hormone (ACTH). Relative Adrenal insufficiency, in which cortisol levels, although possibly elevated in absolute terms, are insuffi- cient to control the inflammatory response in septic shock [25], is defined as an increase in Serum cortisol of less than or equal to 9 lg/dL 1 hour after administration of

250 lg of ACTH and is present in 56% to 77% of Mechanically ventilated patients who have fluid-Refractory septic shock. Annane et al [7] studied the potential benefit of low-dose corticosteroid replacement in 300 patients with septic shock on mechanical ventilation. After an ACTH stimulation test, subjects were randomized to placebo or corticosteroids (hydrocortisone 50 mg IV every 6 hours and the mineralocorticoid, 9a-fludrocortisone 50 lg, once daily by mouth) for 7 days. Administration of cortico- steroids resulted in a 28-day mortality of 63% in the placebo group compared with 53% in the treatment group with Relative adrenal insufficiency who did not respond appropriately to ACTH ( P = .04). Time on vasopressors was also significantly decreased in the treatment group. Low-dose corticosteroid in septic shock has been associ- ated with attenuation in markers of inflammation including interleukin-6, interleukin-8, interleukin-10, and soluble tumor necrosis factor receptors, whereas other proinflam- matory markers such as interleukin-12 were increased [27]. Corticosteroid may also be vital in overcoming tissue- specific corticosteroid resistance [25]. Thus, reduction of the inflammatory response while avoiding significant immunosuppression appears to be associated with im- proved patient outcome.

March 2004 (timing of antibiotics)

As part of the National Pneumonia Project, the Centers for Medicare and Medicaid Services collected medical record data from pneumonia hospitalizations during 1998 and 1999. In 13,771 patients with community-acquired pneumonia, those who received their antibiotics within 4 hours of arrival at the hospital have a decreased mortality (odds ratio, 0.85; 95% confidence interval, 0.74-0.98) and shorter hospital length of stay (odds ratio, 0.90; 95% confidence interval, 0.83-0.96) [28]. In patients with septic shock, there is a significant increase in mortality when antimicrobial therapy is delayed after the onset of hypoten-

sion. Kumar et al [29] examined 2154 septic shock patients in 14 ICUs in Canada and the United States. Each hour of delay in antibiotic administration during the first 6 hours of persistent hypotension was associated with 7.6% increase in mortality (range, 3.6%-9.9%). The odds ratio for mortality was 1.67 (95% confidence interval, 1.12-2.48) if the delay was 1 hour and continued to increase with progressive delays to a maximum value of 92.54 (95% confidence interval, 44.92-190.53) for delays more than 36 hours after the onset of hypotension.

Collaboratives to increase sepsis awareness in the ED

October 2002

In a collaboration between the Society of Critical Care Medicine, the ESICM, and the International Sepsis Forum, the Surviving Sepsis Campaign (SSC) was formed. At the ESICM Annual Meeting in Barcelona, Spain, the SSC began the campaign with the bBarcelona Declaration,Q which aimed to decrease sepsis mortality by 25% via efforts at changing physician behavior toward improved recogni- tion and treatment beginning in the ED.

July 2003

The Emergency Department Sepsis education program and Strategies to Improve Survival Working Group was formed to develop sepsis educational initiatives targeting emergency physicians. The hope was to increase ED awareness for sepsis, leading to improvED patient care and outcome. The first task of this working group was to develop a management guidelines specific to the ED setting. Experts and thought leaders in emergency medicine, infectious disease, and critical care medicine comprised the working work.

Management guidelines

March 2004

A comprehensive evidence-based management guideline for severe sepsis was made by the SSC, which encompass therapies starting in the ED and is completed in the hospital after the patient is admitted [30]. The guideline was endorsed by 11 professional medical societies, including the American College of Emergency Physicians. Some of the therapeutic strategies recommended by the guidelines include early and appropriate antibiotics, early hemodynamic optimization with EGDT, low-dose corticosteroids in patients on vaso- pressors, rhAPC in high-risk patients, low-tidal volume mechanical ventilation [31], and tight glucose control [6,32].

July 2006

A focused guideline for the management of patients with severe sepsis and septic shock in the ED [9] also rec-

ommends early and appropriate antibiotics, source control, EGDT, low-dose corticosteroids, rhAPC, and low-tidal volume mechanical ventilation in the appropriate patients. Most importantly, the guidelines encourage continuing clinician education in sepsis and development of local institutional quality improvement programs to ensure successful implementation of the evidence.

Quality improvement initiatives

October 2003

The Volunteer Hospitals of America Health Foundation partnered with the Johns Hopkins University and the Joint Commission on Accreditation of Healthcare organizations to launch the Transforming the ICU Project to develop, test, and disseminate quality measures for the treatment of severe sepsis. Over a 1-year implementation period, the project achieved a 46.7% reduction in mortality and a 47.3% reduction in hospital length of stay in 20 different ICUs across the United States ( Topics/CriticalCare/Sepsis/ImprovementStories/SepsisCare EntersNewEra.htm, Accessed December 2006).

September 2004

The SSC convened in Sicily, Italy, to develop a resuscitation and a management severe Sepsis Bundle. These bundles should be completed within 6 and 24 hours, respectively, beginning in the ED. The content of the resuscitation bundle received significant input from ACEP delegates to the SSC [11]. The bundle includes action items for early recognition of severe sepsis including lactate screening, cultures to be obtained before antibiotics, early antibiotics, fluid resuscitation, and initiation of EGDT with CVP and Scvo2 monitoring (Fig. 2).

December 2004

The Institute for Healthcare Improvement announced the 100,000 Lives Campaign to save 100,000 patient lives with the implementation of 6 interventions across US hospitals. Four of these interventions were associated with sepsis prevention initiatives and included implementation of rapid response teams, preventing central line infection, preventing surgical infection, and preventing ventilator-associated pneumonia. After 18 months of implementation in over 3000 hospitals in the United States, the campaign resulted in an estimated 122,300 lives saved ( Programs/Campaign, Accessed August 2006).

March 2005

The Joint Commission on Accreditation of Healthcare Organizations developed a preliminary core measures set for severe sepsis based on results of the Transforming the ICU project. However, final approval and implementation of these core measures are pending.

Successful implementations of the evidence

Over the previous 5 years since publication of the revised sepsis definitions, the evidence for new therapeutic strategies, the management guidelines, the launching of various quality improvement initiatives, and implementa- tion of a sepsis protocol beyond antibiotics, specifically EGDT in the ED setting, have been limited at best. However, several efforts were recently published with promising results.

November 2005

In a prospective observational study in 101 hospitalized patients (including 11 patients in the ED) in 2 acute care hospitals in England, Gao et al [33] showed that compliance to the 6-hour resuscitation bundle resulted in a 26% absolute decrease in mortality compared with patients who did not receive the bundle (23% vs 49%; P = .01). Compliance to the 24-hour management bundle resulted in a 21% absolute decrease in mortality, although this is not statistically significant. The compliance rate with the 6-hour bundle and the 24-hour bundle was 52% and 30%, respectively.

January 2006

In a retrospective case series of 24 patients with APACHE II z25 over a 4-month period at Loma Linda University Medical Center in California, we showed the feasibility of EGDT, corticosteroid, and rhAPC administra- tion in the ED setting as Standard care [34]. The EGDT was completed in 54.2% of patients, corticosteroid was admin- istered in 33.3%, and rhAPC was initiated in 33.3% by ED physicians as standard care within a median of 9.5 hours before intensive care consultation for admission. The mortality in patients (8 of 24) who received rhAPC after EGDT and corticosteroid administration was 25% compared with the overall 45.8% mortality of the entire series.

February 2006

In a retrospective cohort study, Trzeciak et al [35] at Cooper University Hospital in New Jersey implemented EGDT as a collaborative emergency medicine/critical care quality improvement initiative in 22 septic shock patients over a 1-year period. Compared to historical controls, patients who received EGDT had 4 days less hospital length of stay and an absolute lower mortality of 25.6% (18.2% vs 43.8%), although not statistically significant.

April 2006

In a prospective cohort study with historical control, Shapiro et al [36] at Beth Israel Deaconess Medical Center in Massachusetts showed that a combination treatment pathway delivered by a bsepsis teamQ including ED and ICU physicians was associated with a nonstatistically significant 0.56 odds of death. The pathway was initiated in the ED for 116 patients and was continued in the ICU,

with treatments including EGDT, early antibiotics, cortico- steroids, rhAPC, and glucose control.

April 2006

In a retrospective cohort study with historical control, Kortgen et al [37] at the University of Saarland in Germany showed that a protocol including EGDT, glucose control, corticosteroid, and rhAPC given in 30 ICU patients was associated with an absolute reduction in mortality of 26% compared to 30 control patients (27% vs 53%; P b .05). Patients receiving the protocol had a statistically significant

0.32 odds of death.

November 2006

In a before-after study performed by Micek et al [38] at Barnes-Jewish Hospital in Missouri, 60 septic shock patients were treated with a standardized hospital order set compared to 60 historical controls. They noted that patients treated with the order set, which was initiated in the ED, received more fluid resuscitation, more appropriate initial antibiotic therapy, and fewer vasopressors. Patients treated with the order set also had an 18% absolute lower mortality compared to controls (30% vs 48%; P = .04).

April 2007

In a prospective cohort examining the implementation of a 6-hour severe sepsis bundle in 330 patients over a 2-year period at Loma Linda University Medical Center in California, we showed that early antibiotics, completion of EGDT and appropriate corticosteroid can be delivered in as standard care by ED physicians [39]. Total compliance to the bundle increased from zero percentage at baseline to 51% at the end of the study period. Patients completing the entire bundle had a 19% absolute lower mortality com- pared to those patients not completing the bundle (21% vs 40%; P b .01).

The future for sepsis in emergency medicine

The best available evidence for the management of severe sepsis and septic shock would suggest that a patient who presents to the ED with an infection and a systemic inflammatory response, coupled with persistent hypoten- sion or lactate level z4 mmol/L, requires urgent appro- priate antibiotics and central venous access to monitor CVP and Scvo2, targeting CVP z8 mm Hg, MAP z65 mm Hg, and Scvo2 z70% with fluid resuscitation, transfusion, vasopressor, and inotrope therapy, as appro- priate. A potential surgical source of infection would also need to be identified and controlled. If the patient has prolonged ED length of stay, then corticosteroid (in a patient on vasopressor or with suspected adrenal insuffi- ciency) and rhAPC (in a patient with high risk for mortality reflected by APACHE II z 25) are administered

if indicated and after careful analysis of the risks and benefits. Further therapies may include glucose control and low-tidal volume mechanical ventilation.

These new strategies appear overwhelming and time consuming compared with the traditional regimen that included only antibiotics and fluids for severe sepsis and septic shock. However, we would argue that we have already spent as much time and resources in caring for trauma and cardiac patients during their golden hours of presentation. It is not a matter of bshould we provide these therapies?,Q but bhow can we do it?Q We propose that a team approach, including emergency physicians and intensive care colleagues, will provide our septic patients with the best care available. Resources required for therapy in septic shock are not any different than resources as aspirin, b-blocker, anticoagulant, thrombolytics, inotrope, and per- cutaneous coronary intervention in a patient with cardio- genic shock from acute myocardial infarction, as well as resources required for central line placement for massive transfusion, chest tube placement, and thoracotomy in a patient with hemorrhagic shock from significant trauma. Furthermore, emergency medicine has now gained a crucial role in sepsis as a disease with respect to patient care, quality improvement initiatives, education, and research. Although there may be obstacles in providing these best practices, we as emergency physicians have the opportunity to significantly impact the course of these endeavors.


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