Updates and Controversies in the Early Management of Sepsis and Septic Shock

Table of Contents

 

For patients in the ED who are suspected of having sepsis, swift, effective management is vital to improving outcomes. This issue reviews the latest evidence on the diagnosis and treatment of sepsis and septic shock:

How do the definitions of sepsis affect treatment decisions – and CMS quality measurements?

Is SOFA scoring in the ED possible? Is quickSOFA scoring helpful?

How can you identify the origin of the infection?

What are the lactate clearance, ScvO₂, and mean arterial pressure values that you must measure and monitor?

What methods of fluid assessment should be used?

Which vasopressor is the first-line choice? Antibiotics?

Is there a role for imaging in sepsis?

Who needs to go to the ICU and who can be discharged?

1. Abstract
2. Case Presentations
3. Introduction
4. Definitions and Terminology
5. Critical Appraisal of the Literature
6. Epidemiology
7. Etiology and Pathophysiology
8. Differential Diagnosis
9. Prehospital Care
10. Emergency Department Evaluation
    1. History
    2. Physical Examination
11. Diagnostic Studies
    1. Laboratory Testing
    2. Lactate Versus Central Venous Oxygen Saturation
    3. Procalcitonin
    4. Imaging
    5. Scoring Systems
12. Treatment
    1. Initial Management
    2. Intravenous Fluids
       1. Fluid Volume and Timing
       2. Fluid Status Assessment
    3. Antibiotics
       1. Antibiotic Timing
       2. Antibiotic Coverage
    4. Vasopressors and Inotropes
       1. Norepinephrine Versus Dopamine
       2. Vasopressin
       3. Epinephrine
       4. Phenylephrine
       5. Angiotensin II
    5. Corticosteroids
    6. Blood Transfusion
13. Special Populations
    1. Pregnant Patients
    2. Patients With End-Stage Renal Disease
14. Controversies and Cutting Edge
    1. Controversies
       1. Fluid Volume
       2. Etomidate
    2. Cutting Edge
15. Disposition
    1. End-of-Life Care
16. Summary
17. Risk Management Pitfalls for Sepsis Management in the Emergency Department
18. Time- and Cost-Effective Strategies
19. Case Conclusions
20. Clinical Pathways
    1. Clinical Pathway for Sepsis Screening in the Emergency Department
    2. Clinical Pathway for Initial Management of Patients With Sepsis
21. Tables
    1. Table 1. Sequential Organ Failure Assessment Score
    2. Table 2. Definitions of Sepsis, Severe Sepsis, and Septic Shock
    3. Table 3. Noninfectious Conditions That May Mimic Sepsis
    4. Table 4. Potential Sources of Infection Associated With Sepsis, by Organ System
    5. Table 5. Historical and Physical Examination Findings Concerning for Sepsis
    6. Table 6. Antibiotic Recommendations by Source of Infection
22. References

Abstract

Sepsis is a common and life-threatening condition that requires early recognition and swift initial management. Diagnosis and treatment of sepsis and septic shock are fundamental for emergency clinicians, and include knowledge of clinical and laboratory indicators of subtle and overt organ dysfunction, infection source control, and protocols for prompt identification of the early signs of septic shock. This issue is a structured review of the literature on the management of sepsis, focusing on the current evidence, guidelines, and protocols.

Case Presentations

A 65-year-old man with COPD and diabetes presents from home with a productive cough (green sputum) for 1 week, dyspnea on exertion, and fever. Albuterol at home provided no relief. His vital signs are: heart rate, 102 beats/min; respiratory rate, 22 breaths/min; blood pressure, 130/89 mm Hg, and SpO₂, 94% on room air. He is speaking in full sentences and does not appear to be in respiratory distress. He has rales at the right lung base, mild wheezes, and tachycardia. Chest radiograph confirms right lower lobe pneumonia. The patient has no recent hospitalizations. You believe that he looks clinically well and may be able to be discharged home with antibiotics, but you are also concerned for sepsis and wonder if this would be a wise decision...

A 45-year-old man with hypertension and prostate cancer in remission presents complaining of 3 days of burning with urination, fevers, and chills. His vital signs are: heart rate, 110 beats/min; respiratory rate, 20 breaths/min; blood pressure, 130/90 mm Hg; SpO₂, 98% on room air; and temperature, 38.4°C (101.2°F). He is alert and fully oriented. His physical exam reveals mild suprapubic tenderness without rebound or guarding and bilateral costovertebral angle tenderness. Lab findings include a WBC count of 18,000 with 5% bands, a creatinine of 1.5 mg/dL, a platelet count of 130 x 10³/mm³, 80 WBCs on urinalysis with positive nitrite and leukocyte esterase, and a serum lactate of 1.2 mmol/L. After receiving ibuprofen and a fluid bolus, the patient feels better and states, “I need to go get my dog!” The nurse asks you if she can remove the IV for the patient to be discharged, which sounds reasonable, but something worries you...

A 70-year-old woman with diabetes mellitus, hypertension, and colon cancer arrives via EMS from a local nursing home for right foot swelling and redness. Paramedics report 2 days of increasing confusion. Her initial blood pressure was 85/50 mm Hg, with a heart rate of 90 beats/min. Her initial glucose was 270 mg/dL. The patient is alert but unable to provide a history. During transfer into her bed, the patient screams in pain as her right leg bumps the bed rail. Your focused exam reveals tachycardia, clear breath sounds, and no acute distress. Her right foot and leg are extremely tender, warm, and erythematous. She has crepitus over the dorsum of the foot and right calf tenderness, but no pretibial edema. The nurse rechecks her vital signs, revealing a blood pressure of 70/40 mm Hg. You order and initiate a fluid bolus. You consider the best antibiotic(s) to start and whether you should initiate pressors before she has received a 30 mL/kg fluid challenge...

Introduction

Sepsis is triggered by a systemic infection and is a life-threatening, dysregulated response to infection.¹ Immune abnormalities induced by invading pathogens or tissue damage produce both the inflammatory and immunosuppressive features of the disease, which causes organ dysfunction and can lead to death. Sepsis may lead to cellular abnormalities and perfusion deficits, causing septic shock. Optimal management strategies for sepsis have been an issue of intense research since a landmark study by Rivers and colleagues published in 2001 identified a 16% mortality reduction with randomization to an early aggressive care bundle termed early goal-directed therapy (EGDT). EGDT involves the administration of fluids, inotropes, and blood, and the achievement of hemodynamic goals to improve tissue oxygenation, as indicated by a central venous oxygen saturation (ScvO₂) > 70%.² After 3 recent multicenter trials failed to validate the results of that study, however, EGDT is no longer recommended.^3-5 Nonetheless, in general, early, aggressive management of sepsis is recommended and has been shown to improve outcomes.^6-9

This issue of Emergency Medicine Practice reviews the recent changes in sepsis criteria, prognosticators, and quality metrics and offers recommendations on the recognition and treatment of sepsis, severe sepsis, and septic shock in the emergency department.

Definitions and Terminology

The diagnosis of sepsis has undergone a metamorphosis since the inception of standardized definitions in 1991.¹⁰ Shifting away from the systemic inflammatory response syndrome (SIRS) criteria previously utilized,¹¹ in 2014 the Society of Critical Care Medicine and the European Society of Intensive Care Medicine convened a task force and, by an expert consensus process, agreed in 2016 on updated definitions and criteria to be tested clinically. The Third International Consensus Definitions for Sepsis and Septic Shock (“Sepsis-3”) redefined sepsis as “life-threatening organ dysfunction caused by a dysregulated host response to infection.”¹

Sepsis-3 also redefined septic shock as “hypotension not responsive to fluid resuscitation,” with the added requirement for vasopressors to maintain a mean arterial pressure (MAP) ≥ 65 mm Hg and a lactate > 2 mmol/L. These new definitions were adopted by the 2016 Surviving Sepsis Campaign: International Guidelines for the Management of Sepsis and Septic Shock.⁹

Sepsis-3 cited new insights into sepsis pathobiology, the lack of sensitivity and specificity of SIRS criteria, and the excessive focus on inflammation as some of the reasons for the changes. The updated definitions in Sepsis-3 emphasize organ dysfunction in the setting of infection, which can be quantified using the sequential (sepsis-related) organ failure assessment (SOFA) score. For expansion of the criteria for scoring SOFA, see Table 1.

Sepsis-3 also derived a bedside assessment tool for sepsis screening in patients with infection who are not in intensive care units (ICUs). Called the quick SOFA (qSOFA) score, it includes 1 point for each of 3 criteria: (1) respiratory rate ≥ 22 breaths/min, (2) altered mental status, or (3) systolic blood pressure (SBP) ≤ 100 mm Hg. A qSOFA score ≥ 2 is suggestive of sepsis.¹² Sepsis-3 recommends that, for a qSOFA score < 2, the full SOFA score, including laboratory results, should be used.¹²

Though the Sepsis-3 tool is more specific for sepsis, using SOFA may be problematic for the emergency clinician. SOFA components can be unfamiliar, with complex ICU-focused scoring on criteria not typically obtained routinely in potentially septic ED patients. These include arterial blood gases for respiratory evaluation and total bilirubin for hepatic dysfunction. In addition, qSOFA has been criticized as insensitive for sepsis screening,^13-21 though it may have increased specificity for mortality^22,23 and predicting organ dysfunction.²⁴

Emergency clinicians should note that the current Centers for Medicare and Medicaid Services (CMS) SEP-1 quality measure, which is used to evaluate institutional sepsis bundle compliance, has not adopted Sepsis-3. The controversial CMS SEP-1 mandate is based on the presence of SIRS criteria, categorizes any infection with organ dysfunction as severe sepsis, and defines septic shock as “hypotension not responsive to fluids or serum lactate ≥ 4 mmol/L regardless of hypotension.”^25,26 Therefore, hospital quality measures assess CMS quality metrics based on the 2001 International Sepsis Definitions Conference¹¹ and not Sepsis-3. There is no indication that this will change, so it is important to know the differing metrics and definitions. A comparison of Sepsis-3 to the 2001 Sepsis definitions as well as CMS SEP-1 criteria are presented in Table 2.

For additional information on calculating the SOFA score, see the online version of the supplement, Calculated Decisions.

For additional information on calculating the Glasgow coma scale score, see the online version of the supplement, Calculated Decisions.

For additional information on calculating the quick SOFA score, see the online version of the supplement, Calculated Decisions.

Critical Appraisal of the Literature

To evaluate clinically relevant articles regarding the diagnosis and early management of sepsis, severe sepsis, and septic shock, a search of the National Library of Medicine PubMed database was performed using the following search terms: sepsis management, septic shock management, and clinical sepsis treatment guidelines, with a date range of 2000 to 2018. Acknowledging the breadth of the sepsis literature, additional specific searches were performed including intravenous fluids, antibiotics, vasopressors, corticosteroids, lactate, lactate clearance, and sepsis. References relevant to prehospital and emergency department (ED) care of septic patients were included. Only adult, human studies were considered, and publications in English (with the exception of 3 Chinese studies on lactate clearance). Current consensus guidelines were also reviewed.

Guidelines have recently been augmented with high-powered randomized clinical trials of sepsis and septic shock that evaluated management strategies, adding to specific recommendations for treatment and resuscitative endpoints. Several studies have recently examined invasive (EGDT) versus less-invasive early resuscitation strategies, and these results have led to recommendations against routine use of invasive strategies that do not confer a mortality benefit. Recommendations for volume of intravenous (IV) fluids, early antibiotics, and infection source control are based on national metrics and observational studies and not randomized clinical trials of early sepsis patients. Randomized trials using serum lactate for both screening and as a resuscitative endpoint support a strong recommendation for its use. Norepinephrine is the current vasopressor of choice, given both randomized trial data and several observational studies. A recent large randomized trial of hydrocortisone for septic shock did not show mortality benefits, but did show improved secondary outcomes.

Risk Management Pitfalls for Sepsis Management in the Emergency Department

1. “I didn’t reassess the patient’s lactate.”

Lactate clearance can aid in assessing a patient’s response to treatment. Persistently elevated lactate may indicate inadequate resuscitation or alternative diagnoses. Particular attention should be given to patients with limited lactate clearance, as persistent elevation is associated with poor outcomes.

5. “I wasn’t sure of the patient’s source of infection, so I waited to give antibiotics.”

Patients with presumed sepsis and hypotension have an increased mortality when antibiotics are delayed. In such cases, administering broad-spectrum antibiotics prior to source confirmation is recommended. For stable patients in whom sepsis is being considered, source-directed antibiotics should be administered as soon as practical and, ideally, within 1 hour of sepsis recognition.

9. “I used dopamine as the first-line vasopressor for septic shock.”

Recent literature and guidelines support norepinephrine as the first-line vasopressor for septic shock. Dopamine is associated with increased risk of arrhythmias and mortality compared with norepinephrine.

Tables

References

Evidence-based medicine requires a critical appraisal of the literature based upon study methodology and number of subjects. Not all references are equally robust. The findings of a large, prospective, randomized, and blinded trial should carry more weight than a case report.

To help the reader judge the strength of each reference, pertinent information about the study, such as the type of study and the number of patients in the study is included in bold type following the references, where available. In addition, the most informative references cited in this paper, as determined by the author, are highlighted.

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2. Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001;345(19):1368-1377. (Randomized clinical trial; 263 patients)
3. Mouncey PR, Osborn TM, Power GS, et al. Trial of early, goal-directed resuscitation for septic shock. N Engl J Med. 2015;372(14):1301-1311. (Randomized clinical trial; 1260 patients)
4. Yealy DM, Kellum JA, Huang DT, et al. A randomized trial of protocol-based care for early septic shock. N Engl J Med. 2014;370(18):1683-1693. (Randomized clinical trial; 1341 patients)
5. Peake SL, Delaney A, Bailey M, et al. Goal-directed resuscitation for patients with early septic shock. N Engl J Med. 2014;371(16):1496-1506. (Randomized clinical trial; 1600 patients)
6. Sterling SA, Puskarich MA, Summers RL, et al. The effect of early quantitative resuscitation on organ function in survivors of septic shock. J Crit Care. 2015;30(2):261-263. (Prospective observational; 301 patients)
7. Jones AE, Shapiro NI, Roshon M. Implementing early goal-directed therapy in the emergency setting: the challenges and experiences of translating research innovations into clinical reality in academic and community settings. Acad Emerg Med. 2007;14(11):1072-1078. (Literature review)
8. Jones AE, Brown MD, Trzeciak S, et al. The effect of a quantitative resuscitation strategy on mortality in patients with sepsis: a meta-analysis. Crit Care Med. 2008;36(10):2734-2739. (Meta-analysis; 1001 patients)
9. Rhodes A, Evans LE, Alhazzani W, et al. Surviving Sepsis Campaign: international guidelines for management of sepsis and septic shock: 2016. Crit Care Med. 2017;45(3):486-552. (Policy)
10. Bone RC, Balk RA, Cerra FB, et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest.1992;101(6):1644-1655. (Guidelines)
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73. Jones AE, Shapiro NI, Trzeciak S, et al. Lactate clearance vs central venous oxygen saturation as goals of early sepsis therapy: a randomized clinical trial. JAMA. 2010;303(8):739-746. (Clinical trial; 300 patients)
74. Jansen TC, van Bommel J, Schoonderbeek FJ, et al. Early lactate-guided therapy in intensive care unit patients: a multicenter, open-label, randomized controlled trial. Am J Respir Crit Care Med. 2010;182(6):752-761. (Clinical trial; 348 patients)
75. Tian HH, Han SS, Lv CJ, et al. [The effect of early goal lactate clearance rate on the outcome of septic shock patients with severe pneumonia]. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue. 2012;24(1):42-45. (Clinical trial; 62 patients)
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