Case Objectives

• Define sepsis, severe sepsis, and septic shock.
• Describe the severe sepsis/septic shock resuscitation bundle.
• Recognize commonly encountered pitfalls in the implementation of the resuscitation bundle.
• List best practices to reduce sepsis-related mortality.

The Case

A 72-year-old woman with pulmonary hypertension, chronic obstructive pulmonary disease (COPD) on home oxygen, and coronary artery disease presented to the hospital with left-sided abdominal pain and shortness of breath. She had been hospitalized for an exacerbation of her COPD 3 weeks prior but had been doing well at home on home oxygen. In the emergency department, she was ill appearing and in some respiratory distress. Her vital signs were notable for a temperature of 38.6° C, heart rate of 115 beats per minute, blood pressure of 104/68 mm Hg, respiratory rate of 28 breaths per minute, and oxygen saturation of 86% on her baseline 2 liters. She was found to have decreased breath sounds at the left base and appeared dehydrated. She had a white blood cell count of 21.4 x 10⁹/L, creatinine of 2.1 mg/dL (up from a baseline of 1.3 mg/dL), a lactate of 3.9 mmol/L, and an international normalized ratio (INR) of 1.5. A chest radiograph revealed an infiltrate in the left lower lobe and she was diagnosed with pneumonia.

The patient was given 1 liter of normal saline in the emergency department. However, because of her history of pulmonary hypertension and coronary artery disease, she was not given any additional intravenous fluids. Blood cultures were drawn, and she received levofloxacin (administered approximately 3 hours after presentation).

She was admitted to the transitional care unit but slowly worsened. Twenty-four hours after admission, her blood cultures were growing methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin was added to her antibiotic regimen. Despite the antibiotics and additional intravenous fluids, she continued to deteriorate. The patient developed respiratory failure requiring mechanical ventilation as well as septic shock requiring vasopressors. Her illness progressed and in discussions with her family, the decision was made to withdraw life-sustaining therapies and allow her to die peacefully. She died on hospital day 4 with her family at her bedside.

The Commentary

The case presented above provides an opportunity to describe errors and pitfalls associated with sepsis management as well as best practices to reduce mortality. In the United States, it is estimated that more than 750,000 adults are diagnosed with sepsis, severe sepsis, or septic shock every year with an associated mortality rate of more than 30%. Attributable costs have been estimated to exceed $10 billion annually.(1,2) As a disease, sepsis is a condition that affects each patient differently but is always initiated by an infection. For example, with the exact same organism in an identical location, one individual may present to the emergency department (ED) with only a mild tachycardia and be sent home, while another may be admitted to the intensive care unit (ICU) and require multiple vasopressors. Regardless of this clinical variability, sepsis always involves activation of the host inflammatory response and, in more serious states, includes dysregulation of the thrombosis-fibrinolysis balance leading to end-organ damage.(3)

Currently, sepsis is defined by the presence of at least two elements of the systemic inflammatory response syndrome (SIRS) with a documented or suspected infection. Elements of SIRS include abnormalities in temperature, heart rate, respiratory rate, white blood cell count, and glucose (Table 1). Severe sepsis is defined as sepsis plus evidence of end-organ damage likely related to the location of the infection or from a dysregulated host response (Table 2). Septic shock is defined as severe sepsis with lactate ≥ 4 mmol/L or hypotension (mean arterial pressure [MAP] 4) In this case, the patient presented to the ED with severe sepsis (fever, tachycardia, suspected pulmonary infection, multiple end-organ dysfunction), but not septic shock as she was not hypotensive and her lactate level was less than 4 mmol/L.

The initial management of severe sepsis and septic shock involves treatment with the resuscitation bundle. The bundle, recently updated in 2013 by the Surviving Sepsis Campaign (SSC) and endorsed by multiple medical societies, includes numerous elements that must be completed in a timely manner.(4) Based on an initial protocol performed by Rivers and colleagues (5), the bundle includes measuring serum lactate levels, drawing blood cultures (preferably before the initiation of antibiotics), treating with appropriate broad-spectrum antibiotics, and in cases of septic shock, targeting central venous pressure (CVP) to 8–12 mm Hg, MAP ≥ 65 mmHg, and superior vena cava oxygen saturation (ScvO2) to 70%. In the ED, antibiotics should be started within 3 hours from the time of presentation. For inpatients, antibiotics should be started within 1 hour from the time of presentation. Regardless of patient location, in the presence of shock, the CVP, MAP, and ScvO2 goals should be achieved within 6 hours. An initial fluid bolus of 30 mL/kg (typically 2–3 liters) is recommended for all patients in septic shock, adding vasopressor(s), starting with norepinephrine, to achieve the MAP goal if fluid resuscitation is not sufficient despite reaching the targeted CVP. In this case, the patient was not initially in septic shock, so initial fluid management was at the discretion of her providers.

In addition to the bundle, other key components of sepsis management include the use of low-tidal volume ventilation in patients with associated adult respiratory distress syndrome (ARDS), corticosteroid (hydrocortisone 50 mg IV every 6 hours for 7–10 days) for refractory shock, red blood cell transfusion to maintain hemoglobin concentration of 7–9 g/dL once tissue hypoperfusion has resolved, and discussing overall goals of care with the patient or surrogate decision-maker.(4)

The initial treatment for severe sepsis requires early administration of appropriate broad-spectrum antibiotic therapy. Empiric antibiotic therapy should be based on local resistance patterns and organism prevalence. In addition, patients with an elevated risk of health care–associated infections or who reside in an area of increased community prevalence of MRSA should be empirically covered with vancomycin or linezolid.(6) Ordering and administering broad-spectrum antibiotics may well be the most important element of the bundle. One study showed that in patients with septic shock, for every hour that appropriate antibiotic therapy was delayed there was an increase in mortality of 7%.(7) In this case, although the timing of the antibiotic administration was appropriate (the patient was in the ED for which the guideline provides a 3-hour window for antibiotic administration), the initial choice, or lack thereof, was not. She should have been immediately started on vancomycin or linezolid as she had been hospitalized 3 weeks prior to her current presentation and was at risk for hospital-acquired organisms, including MRSA.(6) In addition, if she had received levofloxacin during her past hospitalization, an alternative broad-spectrum antibiotic for gram-negative rods from another class should have been chosen (e.g., cefepime or piperacillin/tazobactam).

Errors in sepsis management range from inadvertent and/or purposeful deviations to omissions from resuscitation bundle elements. One must remember that sepsis, severe sepsis, and septic shock are heterogeneous diseases owing to person-to-person variations in host inflammatory responses. Regardless, certain bundle elements, such as checking a lactate, ordering blood cultures, and starting antibiotics are essential. Even if the patient appears well and the concern for a serious infection is low, they should always be performed in patients with sepsis. As stated above, delaying appropriate antibiotic administration can have serious effects. Whether to monitor and treat to target CVP or ScvO2 goals are now left up to the individual practitioner, after two studies published in 2014 did not support the values of these physiologic targets.(8,9)

The time pressure to implement the bundle, especially for inpatients, is real. It is common for a patient to receive all bundle elements, but not within the specified timeframe. In order to maximize timely adherence to the bundle, institutions have created sepsis teams. At the University of California, San Francisco (UCSF), we have created an inpatient sepsis team comprised of a critical care nurse practitioner, a rapid response nurse, and a pharmacist. The primary goal of the critical care nurse practitioner is to communicate with primary physicians and facilitate the ordering of the bundle elements. They also help the primary bedside nurse and rapid response nurse implement the orders within 1-hour as set forth by the guidelines. The pharmacist facilitates rapid antibiotic administration. Since the creation of our sepsis team in fall 2012, our inpatient bundle compliance has increased from less than 5% to near 80%, and sepsis mortality in our institution has fallen from just over 20% to approximately 12%. In the same time period, bundle compliance in our ED has increased from 40% to more than 90% (Figure 1).

Initial recognition is a frequently encountered difficulty in severe sepsis management. Practitioners may often attribute early symptoms to other conditions such as pain, delirium, or medication effects. In addition, severe sepsis and septic shock can mimic other serious conditions such as pancreatitis, cardiogenic shock, and hemorrhagic shock. To mitigate this, the use of a sepsis screening tool is recommended by the SSC. The earlier a patient with severe sepsis is identified, the earlier therapy can be started. The hope is that early recognition and treatment then lead to a decrease in sepsis-related morbidity (new or worsening end-organ dysfunction) and mortality. The SSC provides an example of a screening tool on its Web site (http://www.survivingsepsis.org), but they do not state how often it should be performed or who should perform the screen. I suspect that many institutions that screen for severe sepsis and septic shock have the bedside nurse to complete a checklist at least once a shift. The specific elements of the screening tool are not as important as the fact that it reminds providers to always be vigilant for patients with severe sepsis.

UCSF Medical Center has created a real-time electronic surveillance program to monitor vital signs and laboratory values filed into the electronic medical record (EMR) to generate an alert to nurses and providers when severe sepsis criteria are met, regardless of patient location (ED, ward, ICU). For example, if a patient care assistant entered a patient's vital signs into the EMR with a temperature of 39° C, respiratory rate 18 breaths per minute, heart rate of 104 beats per minute, and blood pressure 80/40 mm Hg, the EMR would generate a sepsis alert. When the patient's chart is subsequently entered by a nurse or other provider, the alert stating the possibility that this patient could have severe sepsis or septic shock (elevated temperature and heart rate with hypotension) would appear (Figure 2).While the automated screening is not perfect, our internal data analysis shows that our alerts have a positive predictive value of around 70%. Institutions should work to develop systematic ways to screen patients in the ED and inpatient units to allow for earlier detection of sepsis.

Lastly, data on bundle compliance and clinical outcomes can be essential to improving sepsis care. Hospital data can be collected and analyzed and feedback on performance should be provided to individuals, units, and the institution as a whole. This can be done via the Patient Quality and Safety Department found in most organizations.

In this case, the ED may or may not have had a severe sepsis or septic shock treatment protocol in place. In many institutions, pre-established protocols and guidelines provide specific recommendations. Had this been the case, the patient would likely have received the appropriate initial antibiotic therapy. Doing so could have dramatically altered her hospital course; whereby she might not have deteriorated and been admitted to the ICU. The case is a reminder of the morbidity and mortality that can be associated with severe sepsis and septic shock and the need for a systematic approach to this disorder.

Take-Home Points

• Sepsis, severe sepsis, and septic shock are on a continuum and are commonly referred to as sepsis.
• Sepsis is a very heterogeneous disease that is difficult to diagnose in its early stages and difficult to treat in its later stages; however, routine screening may aid in early identification.
• In sepsis, early and timely intervention via a well-established bundle (antibiotics, source control, fluid resuscitation, maintenance of MAP) can attenuate its course, thereby possibly decreasing associated mortality, but the mainstay of treatment is supportive care.
• Institutions should create robust patient safety and quality improvement programs to ensure appropriate screening and severe sepsis/septic shock bundle compliance. To be successful, it must have a multidisciplinary approach involving nurses, providers, and hospital administration.

David Shimabukuro, MD

Associate Professor

School of Medicine

University of California, San Francisco

Faculty Disclosure: David Shimabukuro has declared that neither he, nor any immediate member of his family, have a financial arrangement or other relationship with the manufacturers of any commercial products discussed in this continuing medical education activity. In addition, the commentary does not include information regarding investigational or off-label use of pharmaceutical products or medical devices.

References

1. Angus DC, Wax RS. Epidemiology of sepsis: an update. Crit Care Med. 2001;29:S109-S116. [go to PubMed]

2. Levy MM, Artigas A, Phillips GS, et al. Outcomes of the Surviving Sepsis Campaign in intensive care units in the USA and Europe: a prospective cohort study. Lancet Infect Dis. 2012;12:919-924. [go to PubMed]

3. Angus DC, van der Poll T. Severe sepsis and septic shock. N Engl J Med. 2013;369:840-851. [go to PubMed]

4. Dellinger RP, Levy MM, Rhodes A, et al; Surviving Sepsis Campaign Guidelines Committee including the Pediatric Subgroup. Surviving Sepsis Campaign: international guidelines for the management of severe sepsis and septic shock: 2012. Crit Care Med. 2013;41:580-637. [go to PubMed]

5. Rivers E, Nguyen B, Havstad S, et al; Early Goal-Directed Therapy Collaborative Group. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001;345:1368-1377. [go to PubMed]

6. American Thoracic Society; Infectious Disease Society of America. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med. 2005;171:388-416. [go to PubMed]

7. Kumar A, Roberts D, Wood KE, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med. 2006;34:1589-1596. [go to PubMed]

8. Yealy DM, Kellum JA, Huang DT, et al; ProCESS Investigators. A randomized trial of protocol-based care for early septic shock. N Engl J Med. 2014;370:1683-1693. [go to PubMed]

9. Peake SL, Delaney A, Bailey M, et al; ARISE Investigators; ANZICS Clinical Trials Group. Goal-directed resuscitation for patients with early septic shock. N Engl J Med. 2014;371:1496-1506. [go to PubMed]

Tables

Table 1. Elements Associated With the Systemic Inflammatory Response Syndrome.(4)

Systemic Inflammatory Response Syndrome (SIRS)

Temperature > 38.3°C or

Tachypnea

White blood cell (WBC) count > 12 x 109/L or 9/L

Hyperglycemia (glucose > 7.78 mmol/L) in the absence of diabetes

C-reactive protein more than twice the upper limit of normal

Procalcitonin more than twice the upper limit of normal

Table 2. Severe Sepsis: Examples of End-Organ Dysfunction Caused by Infection or Secondary to SIRS Associated With Infection.(4)

Factors to Identify Sepsis-Related Organ Dysfunction

Hypotension with SBP 40 mm Hg from baseline

Acute change in mental status

Lactate > 2 mmol/L

Urinary output

Creatinine > 2 mg/dL

Worsening hypoxemia

Acute lung injury with PaO2/FiO2

Acute lung injury with PaO2/FiO2

Bilirubin > 2 mg/dL

Platelet count 9/L

International normalized ratio > 1.5

Partial thromboplastin time > 60 seconds

MAP: mean arterial pressure
SBP: systolic blood pressure
Reprinted from (4) with permission from Wolters Kluwer Health, Inc.

Figures

Figure 1. UCSF Bundle Compliance and Mortality (Includes All Adult Inpatients and the Emergency Department).

Figure 2. Example of UCSF Severe Sepsis/Septic Shock EMR Alert.