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

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

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  About This Issue

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?

  Issue Information

Author: Faheem Guirgis, MD, FACEP; Lauren Page Black, MD, MPH; Elizabeth L. DeVos, MD, MPH, FACEP

Peer Reviewers: Michael Allison, MD; Jeremy Rose, MD, MPH; Eric M. Steinberg, DO, FACEP

Publication Date: October 1, 2018

CME Expiration Date: October 1, 2021

CME Credits: 4 AMA PRA Category 1 CreditsTM, 4 ACEP Category I Credits, 4 AAFP Prescribed Credits, 4 AOA Category 2A or 2B Credits.

PubMed ID: 30252228

  Issue Features
  Table of Contents
  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



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...



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 - Sepsis Shock - qSOFA - sofa score - lactate - intravenous fluids - Sequential Organ Failure Assessment Score

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 mortality22,23 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.

Sepsis - Sepsis Shock - qSOFA - sofa score - lactate - intravenous fluids - Definitions of Sepsis, Severe Sepsis, and Septic Shock

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.



Sepsis - Sepsis Shock - qSOFA - sofa score - lactate - intravenous fluids - Sequential Organ Failure Assessment Score



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.

  1. Singer M, Deutschman CS, Seymour CW, et al. The Third International Consensus definitions for sepsis and septic shock (Sepsis-3). JAMA. 2016;315(8):801-810. (Policy)
  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)
  11. Levy MM, Fink MP, Marshall JC, et al. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med. 2003;31(4):1250-2156. (Policy)
  12. Seymour CW, Liu VX, Iwashyna TJ, et al. Assessment of clinical criteria for sepsis: for the third International Consensus definitions for sepsis and septic shock (Sepsis-3). JAMA. 2016;315(8):762-774. (Retrospective; 706,399 patients)
  13. Jouffroy R, Saade A, Carpentier A, et al. Triage of septic patients using qSOFA criteria at the SAMU regulation: a retrospective analysis. Prehosp Emerg Care. 2018;22(1):84-90. (Retrospective; 141 patients)
  14. Raith EP, Udy AA, Bailey M, et al. Prognostic accuracy of the SOFA score, SIRS criteria, and qSOFA score for in-hospital mortality among adults with suspected infection admitted to the intensive care unit. JAMA. 2017;317(3):290-300. (Retrospective; 184,875 patients)
  15. Hwang SY, Jo IJ, Lee SU, et al. Low accuracy of positive qSOFA criteria for predicting 28-day mortality in critically ill septic patients during the early period after emergency department presentation. Ann Emerg Med. 2017;71(1):1-9. (Retrospective; 1395 patients)
  16. Henning DJ, Puskarich MA, Self WH, et al. An emergency department validation of the SEP-3 sepsis and septic shock definitions and comparison with 1992 consensus definitions. Ann Emerg Med. 2017;70(4):544-552. (Prospective observational; 7637 patients)
  17. Haydar S, Spanier M, Weems P, et al. Comparison of qSOFA score and SIRS criteria as screening mechanisms for emergency department sepsis. Am J Emerg Med. 2017;35(11):1730-1733. (Retrospective; 199 patients)
  18. Umemura Y, Ogura H, Gando S, et al. Assessment of mortality by qSOFA in patients with sepsis outside ICU: a post hoc subgroup analysis by the Japanese Association for Acute Medicine Sepsis Registry Study Group. J Infect Chemother. 2017;23(11):757-762. (Retrospective; 387 patients)
  19. de Groot B, Stolwijk F, Warmerdam M, et al. The most commonly used disease severity scores are inappropriate for risk stratification of older emergency department sepsis patients: an observational multi-centre study. Scand J Trauma Resusc Emerg Med. 2017;25(1):91. (Observational; 783 patients)
  20. Churpek MM, Snyder A, Han X, et al. qSOFA, SIRS, and early warning scores for detecting clinical deterioration in infected patients outside the ICU. Am J Respir Crit Care Med. 2017;195(7):906-911. (Observational; 30,677 patients)
  21. González del Castillo J, Julian-Jiménez A, González-Martínez F, et al. Prognostic accuracy of SIRS criteria, qSOFA score and GYM score for 30-day-mortality in older non-severely dependent infected patients attended in the emergency department. Eur J Clin Microbiol Infect Dis. 2017;36(12):2361-2369. (Prospective observational; 1071 patients)
  22. Freund Y, Lemachatti N, Krastinova E, et al. Prognostic accuracy of Sepsis-3 criteria for in-hospital mortality among patients with suspected infection presenting to the emergency department. JAMA. 2017;317(3):301-308. (Prospective observational; 879 patients)
  23. Donnelly JP, Safford MM, Shapiro NI, et al. Application of the Third International Consensus Definitions for Sepsis (Sepsis-3) classification: a retrospective population-based cohort study. Lancet Infect Dis. 2017;17(6):661-670. (Retrospective; 30,239 patients)
  24. Park HK, Kim WY, Kim MC, et al. Quick sequential organ failure assessment compared to systemic inflammatory response syndrome for predicting sepsis in emergency department. J Crit Care. 2017;42:12-17. (Retrospective; 1009 patients)
  25. Dellinger RP. The future of sepsis performance improvement. Crit Care Med. 2015;43(9):1787-1789. (Review)
  26. Faust JS, Weingart SD. The past, present, and future of the Centers for Medicare and Medicaid Services Quality Measure SEP-1. Emerg Med Clin North Am. 2017;35(1):219-231. (Review)
  27. Wang HE, Jones AR, Donnelly JP. Revised national estimates of emergency department visits for sepsis in the United States. Crit Care Med. 2017;45(9):1443-1449. (Cross-sectional; 847,868 patients)
  28. Adhikari NKJ, Fowler RA, Bhagwanjee S, et al. Critical care and the global burden of critical illness in adults. Lancet. 2010;376(9749):1339-1346. (Review)
  29. Angus DC, Linde-Zwirble WT, Lidicker J, et al. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med. 2001;29(7):1303-1310. (Retrospective; 192,980 patients)
  30. Mayr FB, Talisa VB, Balakumar V, et al. Proportion and cost of unplanned 30-day readmissions after sepsis compared with other medical conditions. JAMA. 2017;317(5):530-531. (Retrospective; 1,187,697 patients)
  31. Chang DW, Tseng C-H, Shapiro MF. Rehospitalizations following sepsis: common and costly. Crit Care Med. 2015;43(10):2085-2093. (Retrospective; 240,198 patients)
  32. Sterling SA, Puskarich MA, Glass AF, et al. The impact of the Sepsis-3 septic shock definition on previously defined septic shock patients. Crit Care Med. 2017;45(9):1436-1442. (Retrospective; 470 patients)
  33. Driessen RGH, van de Poll MCG, Mol MF, et al. The influence of a change in septic shock definitions on intensive care epidemiology and outcome: comparison of Sepsis-2 and Sepsis-3 definitions. Infect Dis (Lond). 2018;50(3):207-213. (Prospective observational; 632 patients)
  34. Mira JC, Gentile LF, Mathias BJ, et al. Sepsis pathophysiology, chronic critical illness, and persistent inflammation-immunosuppression and catabolism syndrome. Crit Care Med. 2017;45(2):253-262. (Review)
  35. Gentile LF, Cuenca AG, Efron PA, et al. Persistent inflammation and immunosuppression: a common syndrome and new horizon for surgical intensive care. J Trauma Acute Care Surg. 2012;72(6):1491-1501. (Review)
  36. Mathias B, Delmas AL, Ozrazgat-Baslanti T, et al. Human myeloid-derived suppressor cells are associated with chronic immune suppression after severe sepsis/septic shock. Ann Surg. 2017;265(4):827-834. (Prospective observational; 67 patients)
  37. Hotchkiss RS, Monneret G, Payen D. Sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy. Nat Rev Immunol. 2013;13(12):862-874. (Review)
  38. Cerra FB. The systemic septic response: multiple systems organ failure. Crit Care Clin. 1985;1(3):591-607. (Review)
  39. Lagu T, Rothberg MB, Shieh M-S, et al. Hospitalizations, costs, and outcomes of severe sepsis in the United States 2003 to 2007. Crit Care Med. 2012;40(3):754-761. (Retrospective)
  40. Ranieri VM, Thompson BT, Barie PS, et al. Drotrecogin alfa (activated) in adults with septic shock. N Engl J Med. 2012;366(22):2055-2064. (Clinical trial; 1697 patients)
  41. Vincent J-L. International study of the prevalence and outcomes of infection in intensive care units. JAMA. 2009;302(21):2323-2329. (Prospective observational; 14,414 patients)
  42. Opal SM, Garber GE, LaRosa SP, et al. Systemic host responses in severe sepsis analyzed by causative microorganism and treatment effects of drotrecogin alfa (activated). Clin Infect Dis. 2003;37(1):50-58. (Clinical trial; 1690 patients)
  43. Abraham E, Reinhart K, Opal S, et al. Efficacy and safety of tifacogin (recombinant tissue factor pathway inhibitor) in severe sepsis: a randomized controlled trial. JAMA. 2003;290(2):238-247. (Clinical trial; 1690 patients)
  44. Martin GS, Mannino DM, Eaton S, et al. The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med. 2003;348:1546-1554. (Retrospective; 750 million patients)
  45. Takeuchi O, Akira S. Pattern recognition receptors and inflammation. Cell. 2010;140(6):805-820. (Review)
  46. Chan JK, Roth J, Oppenheim JJ, et al. Alarmins: awaiting a clinical response. J Clin Invest. 2012;122(8):2711-2719. (Review)
  47. Angus DC, van der Poll T. Severe sepsis and septic shock. N Engl J Med. 2013;369(9):840-851. (Review)
  48. Boomer JS, To K, Chang KC, et al. Immunosuppression in patients who die of sepsis and multiple organ failure. JAMA. 2011;306(23):2594-2605. (Retrospective; 89 patients)
  49. Walton AH, Muenzer JT, Rasche D, et al. Reactivation of multiple viruses in patients with sepsis. PLoS One. 2014;9(6):e98819. (Clinical trial; 885 patients)
  50. Cunha B. Infectious Diseases in Critical Care Medicine, 2nd Edition. Boca Raton, FL: CRC Press. 2006. (Book)
  51. Femling J, Weiss S, Hauswald E, et al. EMS patients and walk-in patients presenting with severe sepsis: differences in management and outcome. South Med J. 2014;107(12):751-756. (Prospective observational; 378 patients)
  52. Polito CC, Isakov A, Yancey AH, et al. Prehospital recognition of severe sepsis: development and validation of a novel EMS screening tool. Am J Emerg Med. 2015;33(9):1119-1125. (Retrospective cohort; 555 patients)
  53. Herlitz J, Bång A, Wireklint-Sundström B, et al. Suspicion and treatment of severe sepsis. An overview of the prehospital chain of care. Scand J Trauma Resusc Emerg Med. 2012;20(1):42. (Review)
  54. Seymour CW, Rea TD, Kahn JM, et al. Severe sepsis in pre-hospital emergency care: analysis of incidence, care, and outcome. Am J Respir Crit Care Med. 2012;186(12):1264-1271. (Retrospective; 13,249 patients)
  55. Casu S, Häske D. Severe sepsis and septic shock in pre-hospital emergency medicine: survey results of medical directors of emergency medical services concerning antibiotics, blood cultures and algorithms. Intern Emerg Med. 2016;11(4):571-576. (Cross-sectional; 78 participants)
  56. Baez AA, Hanudel P, Wilcox SR. The Prehospital Sepsis Project: out-of-hospital physiologic predictors of sepsis outcomes. Prehosp Disaster Med. 2013;28(6):632-635. (Cross-sectional; 63 patients)
  57. Báez AA, Hanudel P, Perez MT, et al. Prehospital Sepsis Project (PSP): knowledge and attitudes of United States advanced out-of-hospital care providers. Prehosp Disaster Med. 2013;28(2):104-106. (Cross-sectional; 226 participants)
  58. Studnek JR, Artho MR, Garner CL, et al. The impact of emergency medical services on the ED care of severe sepsis. Am J Emerg Med. 2012;30(1):51-56. (Prospective observational; 311 patients)
  59. Wallgren UM, Castrén M, Svensson AEV, et al. Identification of adult septic patients in the prehospital setting. Eur J Emerg Med. 2014;21(4):260-265. (Cross-sectional; 353 patients)
  60. Seymour CW, Cooke CR, Mikkelsen ME, et al. HHS public access. 2014;14(2):145-152. (Secondary analysis of retrospective study; 52 patients)
  61. Bayer O, Schwarzkopf D, Stumme C, et al. An early warning scoring system to identify septic patients in the prehospital setting: the PRESEP Score. Acad Emerg Med. 2015;22(7):868-871. (Retrospective; 375 patients)
  62. Guerra WF, Mayfield TR, Meyers MS, et al. Early detection and treatment of patients with severe sepsis by prehospital personnel. J Emerg Med. 2013;44(6):1116-1125. (Prospective cohort; 112 patients)
  63. Band RA, Gaieski DF, Hylton JH, et al. Arriving by emergency medical services improves time to treatment endpoints for patients with severe sepsis or septic shock. Acad Emerg Med. 2011;18(9):934-940. (Prospective observational; 963 patients)
  64. Uittenbogaard AJM, de Deckere ERJT, Sandel MH, et al. Impact of the diagnostic process on the accuracy of source identification and time to antibiotics in septic emergency department patients. Eur J Emerg Med. 2014;21(3):212-219. (Secondary analysis of prospective observational study; 323 patients)
  65. Hollemans RA, van Brunschot S, Bakker OJ, et al. Minimally invasive intervention for infected necrosis in acute pancreatitis. Expert Rev Med Devices. 2014;11(6):637-648. (Review)
  66. Tong Z, Shen X, Ke L, et al. The effect of a novel minimally invasive strategy for infected necrotizing pancreatitis. Surg Endosc. 2017;31(11):4603-4616. (Clinical trial; 229 patients)
  67. Hosek WT, Laeger TC. Early diagnosis of necrotizing fasciitis with soft tissue ultrasound. Acad Emerg Med. 2009;16(10):1033. (Case report; 1 patient)
  68. Cortellaro F, Ferrari L, Molteni F, et al. Accuracy of point of care ultrasound to identify the source of infection in septic patients: a prospective study. Intern Emerg Med. 2017;12(3):371-378. (Clinical trial; 200 patients)
  69. Vincent J-L, De Backer D. Circulatory shock. N Engl J Med. 2013;369(18):1726-1734. (Review)
  70. Pandharipande PP, Shintani AK, Hagerman HE, et al. Derivation and validation of SpO2/FiO2 ratio to impute for PaO2/FiO2 ratio in the respiratory component of the sequential organ failure assessment score. Crit Care Med. 2009;37(4):1317-1321. (Prospective observational; 2986 patients)
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