Early Care of Adults With Suspected Sepsis in the Emergency Department and Out-of-Hospital Environment: A Consensus-Based Task Force Report

      Introduction

      Sepsis is a major cause of hospital death in the United States (US)
      • Rhee C.
      • Jones T.M.
      • Hamad Y.
      • et al.
      Prevalence, underlying causes, and preventability of sepsis-associated mortality in US acute care hospitals.
      and is associated with over 850,000 annual emergency department visits.
      • Wang H.E.
      • Jones A.R.
      • Donnelly J.P.
      Revised national estimates of emergency department visits for sepsis in the United States.
      Despite advances in care, patients with serious infection continue to have a high inpatient mortality rate, reaching 20% or more in some settings. This makes sepsis and septic shock one of the highest mortality conditions treated in the ED. Additionally, many survivors never fully recover, and instead, long-term morbidities, chronic critical illness, or post-intensive care syndrome develops in them.
      • Gaieski D.F.
      • Edwards J.M.
      • Kallan M.J.
      • et al.
      Benchmarking the incidence and mortality of severe sepsis in the United States.
      ,
      • Wang H.E.
      • Szychowski J.M.
      • Griffin R.
      • et al.
      Long-term mortality after community-acquired sepsis: a longitudinal population-based cohort study.
      Public health and policy efforts seek to reduce the morbidity and mortality associated with sepsis and septic shock through state regulations mandating care, public reporting of hospital performance, the creation of national learning networks, and patient-facing public awareness campaigns.
      • Seymour C.W.
      • Gesten F.
      • Prescott H.C.
      • et al.
      Time to treatment and mortality during mandated emergency care for sepsis.
      • Motzkus C.A.
      • Lilly C.M.
      Accountability for sepsis treatment: The SEP-1 core measure.
      • Venkatesh A.K.
      • Slesinger T.
      • Whittle J.
      • et al.
      Preliminary performance on the new CMS sepsis-1 national quality measure: early insights from the emergency quality network (E-QUAL).
      Sepsis. Centers for Disease Control and Prevention.
      Despite these efforts, death and incomplete recovery in the following 2 years remains elevated.
      • Prescott H.C.
      • Osterholzer J.J.
      • Langa K.M.
      • et al.
      Late mortality after sepsis: propensity matched cohort study.
      ,
      • Iwashyna T.J.
      • Ely E.W.
      • Smith D.M.
      • et al.
      Long-term cognitive impairment and functional disability among survivors of severe sepsis.
      Risk-adjusted mortality varies between regions and hospitals, suggesting that nonstandard clinical treatment pathways leave opportunities to improve.
      • Hatfield K.M.
      • Dantes R.B.
      • Baggs J.
      • et al.
      Assessing variability in hospital-level mortality among U.S. Medicare beneficiaries with hospitalizations for severe sepsis and septic shock.
      ,
      • Walkey A.J.
      • Shieh M.S.
      • Liu V.X.
      • et al.
      Mortality measures to profile hospital performance for patients with septic shock.
      Sepsis care may be most consequential during the earliest phase of treatment. Sepsis in most hospitalized patients in the US (86%) is diagnosed on admission, and up to 80% receive initial care in the ED.
      • Wang H.E.
      • Jones A.R.
      • Donnelly J.P.
      Revised national estimates of emergency department visits for sepsis in the United States.
      ,
      • Rhee C.
      • Dantes R.
      • Epstein L.
      • et al.
      Incidence and trends of sepsis in US hospitals using clinical vs claims data, 2009-2014.
      Furthermore, over 75% of ED sepsis patients are treated by emergency medical services (EMS) providers in the out-of-hospital environment.
      • Wang H.E.
      • Weaver M.D.
      • Shapiro N.I.
      • et al.
      Opportunities for emergency medical services care of sepsis.
      ,
      • Femling J.
      • Weiss S.
      • Hauswald E.
      • et al.
      EMS patients and walk-in patients presenting with severe sepsis: differences in management and outcome.
      Thus, both out-of-hospital and inhospital emergency care are key in identifying sepsis and initiating early care for those with life-threatening infection.
      Many aspects of emergency sepsis care—recognition, prompt and adequate antibiotic therapy, and circulatory support with fluids and vasopressors for those with septic shock—have evidence-based guiding actions that improve outcomes. Given the inherent difficulty in establishing the early diagnosis of sepsis, any guidance must recognize care elements that influence the timeliness and outcomes of care. Aspects that challenge early care include competing ED diagnoses and care, varying levels of evidence for sepsis recommendations, and treating patients with unnecessary therapy when they ultimately have diagnoses other than sepsis.
      Recent policy efforts have intensified the scrutiny placed on clinicians, hospitals, and health systems that deliver sepsis care. In July 2018, the US Centers for Medicare and Medicaid Services (CMS) began public reporting of a national sepsis bundle quality measure, commonly referred to as SEP-1. Early data demonstrated that only half of sepsis patients nationally received the full CMS-recommended bundle for emergency and hospital care.
      • Venkatesh A.K.
      • Slesinger T.
      • Whittle J.
      • et al.
      Preliminary performance on the new CMS sepsis-1 national quality measure: early insights from the emergency quality network (E-QUAL).
      ,
      • Barbash I.J.
      • Davis B.
      • Kahn J.M.
      National performance on the Medicare SEP-1 sepsis quality measure.
      This finding is unsurprising because clinicians often adjust adherence to guideline-based recommendations based on individual patients and local capabilities. The Surviving Sepsis Campaign offers recommendations on comprehensive sepsis care.
      • Rhodes A.
      • Evans L.E.
      • Alhazzani W.
      • et al.
      Surviving sepsis campaign: International guidelines for management of sepsis and septic shock: 2016.
      These efforts support better care and outcomes, but they have also raised concerns for those in acute care settings, such as EDs, because they initially applied to undifferentiated patients before the diagnosis of sepsis could be confirmed.
      Sepsis: ACEP statement on SSC Hour-1 bundle. American College of Emergency Physicians.
      To address controversies and opportunities for improvement in the emergency care of patients with sepsis in acute early care settings, the American College of Emergency Physicians (ACEP) convened a multispecialty task force in 2019. A core group of emergency physicians initially created a list of areas where concerns existed, using their individual experiences and accumulated feedback from the ACEP, and then a group majority agreement identified which topics the panel would address. We sought to identify key elements of early sepsis care, offer insight to aid future efforts, and suggest practical consensus-based approaches to certain parts of ED sepsis management. The group did not intend to create a new or comprehensive set of ED sepsis care guidelines.
      To ensure the inclusion of diverse opinions and perspectives, the ACEP engaged a broad array of experts to address the topics chosen, with the goal of maximizing the consensus of task force recommendations across many audiences. Task force members reviewed existing guidelines, evidence, and medical professional society recommendations; then, a writing committee crafted sections based on an October 2019 in-person meeting of the task force. The consolidated document was shared over 6 months with the full panel for revision and approval. All of the final areas and recommendations reached super majority (75%) approval, eliminating the need for other consensus mechanisms.
      We summarize the task force’s assessment of current knowledge and recommendations in this report. We use a format that addresses common steps in the initial emergency care of adults with suspected sepsis. We focused this work on adult sepsis diagnosis and management given recent collaborative pediatric sepsis care guidelines.
      • Weiss S.L.
      • Peters M.J.
      • Alhazzani W.
      • et al.
      Surviving sepsis campaign international guidelines for the management of septic shock and sepsis-associated organ dysfunction in children.
      The task force product was not created to define a practice standard; we intended to inform physicians’ judgment at the bedside and to help future guideline development by noting areas of concern.

      Recognizing Sepsis and Septic Shock in the First Minutes to Hours of Care

       Principles of Sepsis Recognition

      Key Points:
      • (1)
        Sepsis is a confirmed or suspected infection with new or worsening organ dysfunction and dysregulated host response to infection; it is not defined by a single datum or finding.
        • Septic shock exists in a subset of sepsis patients with circulatory dysfunction, and it confers higher mortality.
        • Septic shock—like sepsis—has a spectrum of disease, ranging from hypotension alone to hypotension requiring vasopressor support with an elevated blood lactate level after initial sepsis resuscitation. All patients with impaired cardiovascular function from sepsis are best managed with early detection and prompt treatment, similar to those with more severe presentations of septic shock.
      • (2)
        Any guideline or care pathway or bundle must accommodate the reality that sepsis detection can be difficult. The clinical findings of sepsis overlap with many other conditions and often require extended time and effort to detect. Therefore, guidance is most applicable when the diagnosis of sepsis is established rather than simply considered as one of multiple potential causes of illness.
        • The differential diagnosis of sepsis in patients is often broad, and accurate diagnosis of sepsis may require advanced or repeated testing and observation to distinguish it from other causes of acute illness.
      Recognizing sepsis early is challenging given the overlapping findings that exist in those with sepsis and those with other acute illnesses. Sepsis is a clinical diagnosis based on a dysregulated response to an infection. Over the last 3 decades, definitions of sepsis from international consensus groups have evolved (Table 1).
      • Bone R.C.
      • Sprung C.L.
      • Sibbald W.J.
      Definitions for sepsis and organ failure.
      • Levy M.M.
      • Fink M.P.
      • Marhsall J.C.
      • et al.
      2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference.
      • Singer M.
      • Deutschman C.S.
      • Seymour C.W.
      • et al.
      The third international consensus definitions for sepsis and septic shock (Sepsis-3).
      Consistent with the current consensus nomenclature, we considered the definition of sepsis to be an infection with new or worsening organ dysfunction; a specific pathogen does not need to be identified for a patient to have sepsis.
      Table 1Evolution of sepsis definitions.
      First Consensus Definitions (1991)
      • Levy M.M.
      • Fink M.P.
      • Marhsall J.C.
      • et al.
      2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference.
      Second Consensus Definitions (2001)
      • Singer M.
      • Deutschman C.S.
      • Seymour C.W.
      • et al.
      The third international consensus definitions for sepsis and septic shock (Sepsis-3).
      Third Consensus Definitions (2016)
      • Marchick M.R.
      • Kline J.A.
      • Jones A.E.
      The significance of non-sustained hypotension in emergency department patients with sepsis.
      InfectionPathology caused by invasion of normally sterile environment by pathogenic microorganismsNo changeNot defined
      SepsisInflammatory response from infection with the SIRS criteria proposed to define an inflammatory responseSuspected or confirmed infection with ≥2 SIRS criteria, as defined below:

      - Temperature of >38 °C or <36 °C

      - Heart rate >90 beats/min

      - Respiratory rate >20 breaths/min or PaO2 <32 mm Hg

      - White blood cell count >12,000 or <4,000 cells/mm3 or >10% band neutrophils
      Organ dysfunction (defined by increase in SOFA score of ≥2) caused by dysregulated response to infection with a threat to survival
      Severe sepsisSepsis associated with organ dysfunctionSepsis with organ dysfunction, defined as any of the following:

      - Hypotension

      - Lactate 2 mmol/L or greater

      - International normalized ratio > 1.5

      - Creatinine > 2.1 mg/dL or urine output < 0.5 mL/kg per hour

      - Platelet count < 110,000/L

      - Oxygen saturation < 90%
      Eliminated (now redundant with “sepsis”)
      Septic shockSepsis with concurrent hypotension despite adequate fluid resuscitation plus perfusion abnormalities, such as elevated lactate levels, low urine output, or altered mental statusSepsis with concurrent hypotension despite adequate fluid resuscitationSepsis with vasopressors required to maintain MAP >65 mm Hg and lactate >2 mmol/L after fluid resuscitation
      SIRS, Systemic inflammatory response syndrome.
      Septic shock is a severe form of sepsis with cardiovascular dysfunction, usually manifested as hypotension. Recent consensus definition efforts (Sepsis-3)
      • Singer M.
      • Deutschman C.S.
      • Seymour C.W.
      • et al.
      The third international consensus definitions for sepsis and septic shock (Sepsis-3).
      have narrowed the definition of septic shock to those with hypotension requiring vasopressor therapy plus an elevated blood lactate level (2 mmol/L or above) after initial resuscitation (see later discussion) to identify a subgroup at very high risk of mortality. Previous definitions used broader inclusions for defining septic shock, including those with hypotension alone.
      We acknowledge that sepsis and septic shock exist on a continuum and that patients with infection-induced cardiovascular failure benefit from prompt recognition and care, no matter what current term defines their status. We also recognize that patients with infection-induced hypotension are an important population in the out-of-hospital and ED settings, as vital signs alone are harbingers of the need for time-sensitive care, even if these patients fail to meet the Sepsis-3 definition of septic shock. A singular episode of hypotension portends a worse outcome, underscoring the need for an inclusive early approach to identifying patients at higher risk of death or harm from sepsis.
      • Marchick M.R.
      • Kline J.A.
      • Jones A.E.
      The significance of non-sustained hypotension in emergency department patients with sepsis.
      No single test accurately and reliably establishes a diagnosis of sepsis. Although some patients present with overt findings of sepsis, many have vague symptoms or examination features that overlap with those of other conditions (eg, tachycardia, tachypnea, laboratory changes, and other findings). Sepsis can be difficult to recognize in the immunocompromised, the elderly, and those presenting very early in the course of illness, when intact or robust compensatory responses may shroud overt signs.
      The differential diagnoses of both sepsis and septic shock include other causes of organ dysfunction, many of which require different methods of care. For example, 20% to 40% of patients with suspected sepsis in the ED are ultimately diagnosed with a noninfectious sepsis mimic, such as pulmonary embolism, cardiogenic shock, or overdose.
      • Heffner A.C.
      • Horton J.M.
      • Marchick M.R.
      • et al.
      Etiology of illness in patients with severe sepsis admitted to the hospital from the emergency department.
      • Klouwenberg P.M.
      • Cremer O.L.
      • van Vught L.A.
      • et al.
      Likelihood of infection in patients with presumed sepsis at the time of the intensive care unit admission: a cohort study.
      • Burston J.
      • Adhikari S.
      • Hayen A.
      • et al.
      A role for antimicrobial stewardship in clinical sepsis pathways: a prospective interventional study.
      These patients with sepsis mimics rarely benefit from all aspects of sepsis-directed care. Anchoring on a diagnosis of sepsis early in the illness course can result in missed or delayed diagnosis and treatment of the true cause of acute illness.
      The care of those with sepsis should be monitored for impact to identify best practices as well as opportunities for improvement. Sepsis outcomes worsen with delays in care, but giving sepsis-specific care when sepsis does not exist may not offer benefit and can risk harm, though the latter is not routinely assessed. Further complicating surveillance are initiatives that utilize the easily available time of ED arrival as the starting point for sepsis care, which both ignores sepsis mimics and creates quality benchmarks of limited clinical validity. As a result, and in response to input from the ACEP and others in emergency care, the Surviving Sepsis Campaign revised the start time of bundle initiation from the easily identified time of ED arrival to the more difficult to track—but more relevant—time of sepsis diagnosis.
      We support a paradigm of defining sepsis and septic shock terms and care steps for use across all care settings and clinicians of different specialties, done best with meaningful contribution by all key stakeholders.

       Early Screening and Detection of Those With Sepsis

      Key Points:
      • (1)
        Standardized early sepsis screening tools may improve sepsis recognition and care. However, there is no validated evidence-based tool or strategy to reliably accomplish this goal in the ED or out-of-hospital setting.
      Many performance improvement programs aim to improve early sepsis recognition through systematic screening manually or in the electronic health record.
      • Walters E.
      Raising awareness for sepsis, sepsis screening, early recognition, and treatment in the emergency department.
      • Alsolamy S.
      • Al Salamah J.
      • Al Thagafi M.
      • et al.
      Diagnostic accuracy of a screening electronic alert tool for severe sepsis and septic shock in the emergency department.
      • Gatewood M.O.
      • Wemple M.
      • Greco S.
      • et al.
      A quality improvement project to improve early sepsis care in the emergency department.
      Presently, although many can improve certain care tasks, there are no early screening systems that are demonstrably effective in improving outcomes of this critical task. Many screening methods tailor activities to the needs and capabilities of individual hospitals or health systems rather than to broadly identifying those in need of sepsis-related interventions. Some early sepsis screening tools have improved timeliness of care, but insight into reliability and patient-focused outcomes is lacking. This question creates uncertainty regarding whether the key feature leading to care improvement is the use of a specific screening tool or the inclusion of healthier patients in the sepsis denominator, or whether the general act of performing quality improvement activities simply increases recognition of sepsis.
      • Rhee C.
      • Klompas M.
      Sepsis trends: increasing incidence and decreasing mortality, or changing denominator?.
      It is incumbent on clinicians to understand which elements of screening lead to improved outcomes and to embrace those that are best supported.

      Initial Care Steps in the Emergency Department and the Out-of-Hospital Environment

       Principles of Early Sepsis Management

      Key Points:
      • (1)
        History and physical examination may help to detect infection and organ dysfunction.
      • (2)
        Once sepsis is recognized, prompt action to treat infection and reverse or prevent hypotension and hypoperfusion is important. However, time thresholds for care must be based on distinguishing sepsis from other clinical diagnoses.
        • Accruing evidence of infection, organ dysfunction, and hypotension or hypoperfusion requires longitudinal observation, meaning thresholds based on searchable administrative times alone may not be feasible.
      We agree that prompt evaluation and management of patients with suspected sepsis in the out-of-hospital setting and ED are important. Whereas current evidence supports that sepsis care is time sensitive, our review identified a variety of elements that may affect how rapidly the diagnosis of sepsis can be established, especially when presenting signs and symptoms suggest alternate diagnoses. Accordingly, we offer readily deployable and early action for patient care while sepsis is being discerned from other competing diagnoses (Table 2). Once the diagnosis of sepsis is confirmed, current guidelines offer thresholds for time-based action to support optimal care.
      Table 2Key principles in the initial management of patients with suspected sepsis in the out-of-hospital setting and emergency department.
      TopicOut-of-HospitalEmergency Department
      Evaluation for source of infectionObtain historical elements of when the patient became ill and time course of symptoms.Focused history and physical examination. Recommended testing includes bacterial and viral specimens for culture or analysis, urinalysis, chest x-ray, and selective cross-sectional imaging as directed by presenting signs, symptoms, and the results of other diagnostic tests.
      Severity assessmentObtain vital signs. Administer supplemental oxygen to maintain SpO2 ≥92%.Assess for organ dysfunction by physical examination and laboratory assessment. Recommended evaluation for most patients includes blood lactate, complete blood count with differential, chemistry panel, liver function tests, mental status assessment, cardiovascular assessment (heart rate, blood pressure), and respiratory assessment (rate, work of breathing, SpO2). Administer supplemental oxygen to maintain ≥92%.
      Treatment and prevention of hypotensionEstablish whether hypotension (typically defined as a MAP <65 mm Hg or SBP <90–100) is present.Use intravenous fluids and/or vasopressors to resolve hypotension/hypoperfusion.
      Intravenous fluidWe recommend using a bolus of isotonic crystalloid (a balanced crystalloid solution is preferred) in patients with systolic blood pressure <100 mm Hg and without signs of fluid overload. An initial administration of 500–1,000 mL of isotonic crystalloid is an acceptable, common approach.Current data do not identify a specific fluid volume that optimizes patient outcomes. In patients with SBP <100 mm Hg, MAP <65 mm Hg, or other signs of hypoperfusion and without signs of fluid overload, initial administration of 500–2,000 mL (or up to approximately 30 mL/kg) of isotonic crystalloid is an acceptable, common approach. Frequent assessments of fluid status and assessment of the hemodynamic response to fluid administration should guide whether additional fluid is given. Balanced crystalloid solutions are the preferred type of fluid.
      VasopressorsInsufficient data are available to make a recommendation about administration of out-of-hospital vasopressors.The timing of vasopressor use—after how much volume and based on what response—is not evidence-based. Many initiate a vasopressor infusion (norepinephrine recommended as first-line therapy) for profound shock or persistent hypotension after initial intravenous fluid delivery. Earlier vasopressor use before completing a set volume of fluid administration may be an acceptable alternative. Vasopressors may be administered by peripheral intravenous line or intraosseous line without central venous access. Titrate vasopressors to maintain MAP ≥65 mm Hg.
      AntibioticsInsufficient data are available to make a recommendation about administration of out-of-hospital antibiotics.We recommend prompt administration of antibiotics in the ED, but we reserve very short time thresholds for those with infection and shock and note there are insufficient data to recommend a specific time threshold for administration of antibiotics. In a patient without a confirmed source of infection, broad-spectrum antibiotics with activity against gram-negative and gram-positive bacteria according to local antibiotic susceptibility should be administered. Patients with identified sources of infection (eg, pneumonia, UTI) may have therapy targeted according to source-specific guidelines.
      Infection source controlNo specific action.Remove accessible temporary devices that appear infected (eg, temporary urinary and vascular catheters). Consult surgical or procedural specialists for evaluation of patients with infectious sources potentially amenable to procedural source control (eg, abscess, necrotizing soft tissue infection, toxic megacolon).
      SBP, Systolic blood pressure; UTI, urinary tract infection.
      Many patients with sepsis have relative or absolute hypovolemia. A variety of management strategies help address plasma volume expansion and other resuscitative actions in those with sepsis and septic shock. One such resuscitation strategy by Rivers et al
      • Rivers E.
      • Nguyen B.
      • Havstad S.
      • et al.
      Early goal-directed therapy in the treatment of severe sepsis and septic shock.
      is termed “early goal-directed therapy,” which delineates an algorithmic approach to the recognition and management of patients with sepsis and either hypotension or elevated lactate levels; the Rivers et al did not study all types of patients with sepsis. Early goal-directed therapy relied on central venous pressure, mean arterial pressure (MAP), central venous oxygen saturation, and hematocrit to guide resuscitation. That seminal trial showed that early recognition and resuscitation improved outcomes, but 3 subsequent large multicenter trials spanning from 2008 to 2014 comparing early goal-directed therapy with usual care did not demonstrate improved outcomes with early goal-directed therapy.
      • Yealy D.M.
      • Kellum J.A.
      • et al.
      ProCESS Investigators
      A randomized trial of protocol-based care for early septic shock.
      • Mouncey P.R.
      • Osborn T.M.
      • Power G.S.
      • et al.
      Trial of early, goal-directed resuscitation for septic shock.
      • Peake S.L.
      • et al.
      ARISE Investigators, ANZICS Clinical Trials Group
      Goal-directed resuscitation for patients with early septic shock.
      It is important to note that the latter trials employed nonalgorithmic but still early recognition and resuscitation patterns adopted in the interim as “usual care.” Therefore, the key aspects of early goal-directed therapy—early recognition and prompt resuscitation—are now foundational to septic shock care.

       Out-of-Hospital Care

      Key Points:
      • (1)
        EMS providers can expedite sepsis care through a focused history and by obtaining corroborating data prior to transport.
      • (2)
        Selecting and rapidly transporting sepsis patients to an ED capable of providing necessary early sepsis care are important factors in out-of-hospital sepsis care.
      • (3)
        Out-of-hospital antibiotic therapy has the potential to improve outcomes, but it is not currently supported by data and cannot yet be recommended for routine use.
      In the out-of-hospital setting, a key priority is rapidly transporting a patient with potential sepsis to a site capable of providing the care needed. Obtaining a focused history from the patient, family members, caregivers, and others immediately available at the time of patient transport can aid in identifying the cause and severity of illness. EMS providers should communicate this history to ED personnel during the care transition to ensure timely sepsis diagnosis and therapy. Other field diagnostic testing is currently of unproven benefit and is not commonly available. Although giving antibiotics during this very early care interval has theoretic benefit for those with sepsis, the accurate identification of the best patients to receive this therapy is difficult, and the current data do not support a clear benefit of this approach.
      • Alam N.
      • Oskam E.
      • Stassen P.M.
      • et al.
      Prehospital antibiotics in the ambulance for sepsis: a multicentre, open label, randomized trial.
      Future research assessing out-of-hospital diagnostics and interventions may alter recommendations for field care.

       Evaluation for Source of Infection

      Key Points:
      • (1)
        We support obtaining blood cultures in the ED without delaying care in those with suspected sepsis.
      • (2)
        In those without an identified source of infection, we support obtaining a chest x-ray and urinalysis (with urine culture if urinalysis is suggestive of infection) in the ED.
      • (3)
        We support sampling possible infection sources based on medical history, symptoms, and physical examination findings (eg, cerebrospinal fluid, peritoneal fluid, wounds).
      • (4)
        Targeted computed tomography (CT) based on clinical suspicion is preferred to routine whole-body imaging.
      In the ED, evaluation for the source of infection should include a history and physical examination, with a review of available and relevant medical records. If a source is not identified with initial examination and testing, we recommend that providers reassess and focus attention on areas of potential cryptic infection that can be difficult to fully examine, including the genitourinary region, perianal region, and sites of medical devices and indwelling catheters.
      • Mayr F.B.
      • Yende S.
      • Linde-Zwirble W.T.
      • et al.
      Infection rate and acute organ dysfunction risk as explanations for racial differences in severe sepsis.
      Although sending samples for culture does not affect initial treatment, isolation of a pathogen from samples collected early and prior to antibiotics can provide source confirmation and enhance appropriate antibiotic tailoring because cultures taken after antibiotics have substantially lower yields.
      • Garnacho-Montero J.
      • Gutiérrez-Pizarraya A.
      • Escoresca-Ortega A.
      • et al.
      De-escalation of empirical therapy is associated with lower mortality in patients with severe sepsis and septic shock.
      • Dellit T.H.
      • Owens R.C.
      • McGowan J.E.
      • et al.
      Infectious Diseases Society of America and the Society for Healthcare Epidemiology ProCESS of America guidelines for developing an institutional program to enhance antimicrobial stewardship.
      • Cheng M.P.
      • Stenstrom R.
      • Paquette K.
      • et al.
      Blood culture results before and after antimicrobial administration.
      We recommend collecting blood cultures as early as feasible and before administration of antibiotics, unless culture collection will delay antibiotic administration. Taking 2 sets of blood cultures (1 aerobic bottle and 1 anaerobic bottle in each set) obtained from separate sites over a short time period is common practice, using techniques to minimize the risk of contamination.
      • Baron E.J.
      • Miller J.M.
      • Weinstein M.P.
      • et al.
      A guide to utilization of the microbiology laboratory for diagnosis of infectious diseases: 2013 recommendations by the Infectious Diseases Society of America (IDSA) and the American Society for Microbiology (ASM)(a).
      ,
      • Self W.H.
      • Speroff T.
      • Grijalva C.G.
      • et al.
      Reducing blood culture contamination in the emergency department: an interrupted time series quality improvement study.
      In a patient with a suspected infection involving an indwelling vascular catheter, collecting one set of blood cultures from the catheter in addition to peripheral blood cultures (with time-to-positivity testing) is one strategy to aid diagnosis of a catheter-related bloodstream infection.
      Pneumonia and urinary tract infection are the 2 most common infection sources in sepsis.
      • Mayr F.B.
      • Yende S.
      • Linde-Zwirble W.T.
      • et al.
      Infection rate and acute organ dysfunction risk as explanations for racial differences in severe sepsis.
      Absent a clear alternative source, we support chest imaging (usually with chest x-ray) and urinalysis (with subsequent urine culture) in the appropriate clinical circumstances. Additional testing for sources of infection is based on history and examination. For patients presenting with respiratory symptoms when local influenza or severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is prevalent, many clinicians choose molecular viral testing (eg, reverse transcriptase polymerase chain reaction, or RT-PCR) of a nasopharyngeal or respiratory specimen in any patient with respiratory symptoms, fever, or other symptoms of the prevalent infection.
      • Uyeki T.M.
      • Bernstein H.H.
      • Bradley J.S.
      • et al.
      Clinical practice guidelines by the Infectious Diseases Society of America: 2018 update on diagnosis, treatment, chemoprophylaxis, and institutional outbreak management of seasonal influenza.
      In patients with suspected infection and signs of clinical instability (eg, hypotension), we recommend starting antibiotic therapy promptly after blood cultures are drawn. This often means that some culture specimens, such as urine, cerebrospinal fluid, or synovial fluid, follow an initial dose of antibiotics in the ED.
      CT may detect other infectious sources.
      • Upchurch C.P.
      • Grijalva C.G.
      • Wunderink R.G.
      • et al.
      Community-acquired pneumonia visualized on CT scans but not chest radiographs: pathogens, severity, and clinical outcomes.
      • Claessens Y.E.
      • Debray M.P.
      • Tubach F.
      • et al.
      Early chest computed tomography scan to assist diagnosis and guide treatment decision for suspected community-acquired pneumonia.
      • Emmi V.
      • Sganga G.
      Clinical diagnosis of intra-abdominal infections.
      We advocate for targeted use of CT based on likely sources of infection after a clinical assessment rather than untargeted “whole-body” CT. Early ED identification of a culprit infection source also supports rapid source control for abscess, intestinal perforation, infected medical prosthesis, or necrotizing soft tissue infection.

       Severity Assessment

      Key Points:
      • (1)
        Clinicians should use multiple clinical and laboratory findings to detect sepsis and guide care.
      • (2)
        We support initially measuring blood lactate levels in the ED (venous or arterial) and repeating lactate measurement after initial resuscitation only if elevated above 4 mmol/L or if there is suspicion of clinical deterioration.
      • (3)
        After noting whether hypotension is present, no scoring system accurately stratifies individual sepsis patient risk at the earliest stages of care. We recommend assessment of sepsis severity through identifying acute organ dysfunction; collecting data needed to calculate the Sequential Organ Failure Assessment (SOFA) score is one reasonable systematic approach.

       Lactate

      Blood lactate level is not a specific diagnostic test for sepsis, and elevations can exist for many reasons.
      • Kraut J.A.
      • Madias N.E.
      Lactic acidosis.
      Nonetheless, lactate elevations correlate with a higher risk of short-term mortality.
      • Singer M.
      • Deutschman C.S.
      • Seymour C.W.
      • et al.
      The third international consensus definitions for sepsis and septic shock (Sepsis-3).
      ,
      • Shankar-Hari M.
      • Phillips G.S.
      • Levy M.L.
      • et al.
      Developing a new definition and assessing new clinical criteria for septic shock: for the third international consensus definitions for sepsis and septic shock (sepsis-3).
      We endorse the use of venous lactate specimens because this approximates arterial lactate values, is supported by most sepsis literature, and facilitates timelier sampling.
      Convenient thresholds used to note abnormal elevation in blood lactate are more than 2.0 mmol/L (evidence of cellular dysfunction) and more than 4.0 mmol/L (evidence of more severe cellular dysfunction).
      • Singer M.
      • Deutschman C.S.
      • Seymour C.W.
      • et al.
      The third international consensus definitions for sepsis and septic shock (Sepsis-3).
      ,
      • Khosravani H.
      • Shahpori R.
      • Stelfox H.T.
      • et al.
      Occurrence and adverse effect on outcome of hyperlactatemia in the critically ill.
      ,
      • Shapiro N.I.
      • Howell M.D.
      • Talmor D.
      • et al.
      Serum lactate as a predictor of mortality in emergency department patients with infection.
      Just as increasing lactate concentration correlates with a worsening clinical status and an increased risk of death, declining lactate levels with resuscitation are favorable indicators.
      • Kraut J.A.
      • Madias N.E.
      Lactic acidosis.
      ,
      • Jones A.E.
      • Shapiro N.I.
      • Trzeciak S.
      • et al.
      Lactate clearance vs central venous oxygen saturation as goals of early sepsis therapy: a randomized clinical trial.
      We agree that obtaining an initial lactate level aids in characterizing sepsis patients, but the most convincing data of benefit from repeat measurements studied those with an initial lactate level of at least 4 mmol/L.
      • Jones A.E.
      • Shapiro N.I.
      • Trzeciak S.
      • et al.
      Lactate clearance vs central venous oxygen saturation as goals of early sepsis therapy: a randomized clinical trial.
      The optimal timing to define changes in lactate level that indicate meaningful improvement is not known, but a common practice includes measuring lactate in 2-hour intervals, with a 10% relative decline in lactate between measurements indicating improvement.
      • Jones A.E.
      • Shapiro N.I.
      • Trzeciak S.
      • et al.
      Lactate clearance vs central venous oxygen saturation as goals of early sepsis therapy: a randomized clinical trial.

       SOFA Score

      The SOFA scoring system organizes and classifies sepsis-associated organ dysfunction. Like many similar tools, the trajectory of the SOFA score has more prognostic and therapeutic utility than a singular measurement.
      • Singer M.
      • Deutschman C.S.
      • Seymour C.W.
      • et al.
      The third international consensus definitions for sepsis and septic shock (Sepsis-3).
      ,
      • Vincent J.L.
      • Moreno R.
      • Takala J.
      • et al.
      The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine.
      Using the SOFA system to characterize sepsis severity also facilitates serial assessments and communication between providers by supplying a shared nomenclature.
      The SOFA score assesses dysfunction across 6 organ systems—respiratory, coagulation, liver, cardiovascular, central nervous, and renal—with a score for each system, ranging from 0 (no dysfunction) to 4 (most severe dysfunction) (Table 3). The total SOFA score is the sum of the component scores for each of the 6 systems, resulting in a range from 0 (no dysfunction) to 24 (most severe dysfunction).
      Table 3The Sequential Organ Failure Assessment (SOFA) scoring system modified for use in the ED. Modified from Singer et al
      • Marchick M.R.
      • Kline J.A.
      • Jones A.E.
      The significance of non-sustained hypotension in emergency department patients with sepsis.
      and Vincent et al.
      • Vincent J.L.
      • Moreno R.
      • Takala J.
      • et al.
      The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine.
      .
      System (Measurement)ScoreRecommended Action in ED
      01234
      RespiratoryAssess SpO2 without supplemental oxygen if feasible. Apply oxygen to maintain SpO2 ≥92%. Note SpO2 and oxygen delivery once SpO2 has stabilized at ≥92%.
      PaO2/FiO2 ratio≥400300–399200–299 or <200 without invasive or noninvasive ventilation100–199 with invasive or noninvasive ventilation<100 with invasive or noninvasive ventilation
      Approximate SpO2 and oxygen delivery
       Without invasive or noninvasive ventilationSpO2 ≥97% on room airSpO2 92%–96% on room airSupplemental O2 to maintain SpO2 ≥92%NANA
       With invasive or noninvasive ventilationSpO2 97%–100%SpO2 92%–96% on FiO2=0.3FiO2 0.31–0.69 to maintain SpO2 ≥92%FiO2 ≥0.7 to maintain SpO2 ≥92%
      CoagulationObtain CBC with platelet count.
      Platelets (103/μL)≥150100–14950–9920–49<20
      LiverObtain liver function tests with total bilirubin concentration.
      Total bilirubin (mg/dL)<1.21.2–1.92.0–5.96.0–11.9>12.0
      CardiovascularAssess initial MAP. Initiate fluid resuscitation. Administer vasopressors as needed to maintain MAP ≥65 mm HG.
      MAP and vasopressor useMAP ≥70 without vasopressorsMAP <70 without vasopressorsDopamine <5 or dobutamine any doseDopamine 5.1–15, epinephrine ≤0.1, or norepinephrine ≤0.1Dopamine >15, epinephrine >0.1, or norepinephrine >0.1
      Central nervous systemNote highest Glasgow Coma Scale in ED (after resuscitation).
      Glasgow Coma Scale1513–1410–126–9<6
      RenalObtain chemistry panel with creatinine concentration.
      Serum creatinine (mg/dL)<1.21.2–1.92.0–3.43.5–4.9≥5.0
      CBC, Complete blood count; NA, not applicable.
      We support testing to assess organ function, which also allows SOFA scoring. Collecting SOFA score data (Table 3) entails an assessment of oxygenation, a complete blood count with platelet count, liver function tests with serum total bilirubin concentration, blood pressure checks and the need for vasopressors, the Glasgow Coma Scale score, and a basic chemistry panel with serum creatinine concentration. Using the original SOFA criteria, scoring respiratory system dysfunction depends on availability of a PaO2 value to calculate a PaO2/FiO2 ratio. We do not advocate performing an arterial blood gas only to obtain PaO2 for the purposes of calculating a respiratory SOFA score. Patients with a change in SOFA score of at least 2 points compared with baseline (before illness) have life-threatening organ dysfunction and an inhospital mortality risk of at least 10%.
      • Singer M.
      • Deutschman C.S.
      • Seymour C.W.
      • et al.
      The third international consensus definitions for sepsis and septic shock (Sepsis-3).
      ,
      • Seymour C.W.
      • Liu V.X.
      • Iwashyna T.J.
      • et al.
      Assessment of clinical criteria for sepsis: for the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3).
      An adaptation of the SOFA score may make organ failure‒based scoring more feasible for ED assessment (Table 3). In Table 3, we included pulse oximetry (SpO2) values on specific oxygen flow rates that approximate PaO2/FiO2 thresholds in the original SOFA scoring system.
      • Brown S.M.
      • Duggal A.
      • Hou P.C.
      • et al.
      Nonlinear imputation of PaO2/FIO2 from SpO2/FIO2 among mechanically ventilated patients in the ICU: a prospective, observational study.
      SpO2 and supplemental oxygen flow rate do not precisely correlate with PaO2 and FiO2; however, these parameters can provide an estimate of the severity of respiratory dysfunction that is much more feasible in common ED practice. Another option is the modified SOFA, tested in the ED.
      • Grissom C.K.
      • Brown S.M.
      • Kuttler K.G.
      • et al.
      A modified sequential organ failure assessment score for critical care triage.
      ,
      • Raymond N.J.
      • Nguyen M.
      • Allmark S.
      • et al.
      Modified sequential organ failure assessment sepsis score in an emergency department setting: retrospective assessment of prognostic value.
      The “quick SOFA” (qSOFA) scoring tool sought to simplify the key aspects of SOFA scoring for identification of patients at highest risk for poor outcomes. Drawn from ED and hospitalized patients, the qSOFA score identifies infected patients at higher risk of death if 2 or more of the following features are present: respiratory rate of at least 22 breaths/min, altered mental status, and systolic blood pressure of at least 100 mm Hg; these vital sign abnormalities are not unique to patients with sepsis.
      • Singer M.
      • Deutschman C.S.
      • Seymour C.W.
      • et al.
      The third international consensus definitions for sepsis and septic shock (Sepsis-3).
      ED-based validation studies show that qSOFA is less sensitive and more specific for short-term mortality than the 2001 systemic inflammatory response syndrome criteria.
      • Levy M.M.
      • Fink M.P.
      • Marhsall J.C.
      • et al.
      2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference.
      Screening with qSOFA is potentially useful for identifying patients at the highest risk for clinical deterioration and need for intensive care, but this tool is not sensitive enough to be used as the sole strategy for sepsis screening. It also was not intended to identify patients with infection, as it was developed to assess outcomes in patients already diagnosed with infection. Only 1 of every 3 patients who are qSOFA-positive on admission has infection, and 1 in 6 has sepsis. The qSOFA score also has low sensitivity for identifying suspected infection and sepsis, and its prognostic significance is not specific to infection. More sensitive and specific tools for sepsis screening and risk stratification are needed.
      • Anand V.
      • Zhang Z.
      • Kadri S.S.
      • et al.
      Epidemiology of quick sequential organ failure assessment criteria in undifferentiated patients and association with suspected infection and sepsis.
      Based on the absence of a single optimal screening method to accurately capture those with sepsis, we think clinicians should employ multiple complementary approaches to identify those with infection accompanied by organ dysfunction to aid care.

       Intravenous Fluid and Timing of Vasopressors

      Key Points:
      • (1)
        We agree with delivering an intravenous (IV) fluid bolus during initial management of patients who have hypotension or findings of hypoperfusion absent signs of fluid overload.
        • We do not support a prespecified volume or body mass‒adjusted volume of fluid for all patients, though we recognize many patients benefit from 30 mL/kg of crystalloid. Patient response may serve as the best indicator of the appropriateness of fluid resuscitation volume, rather than the delivery of a prespecified volume.
        • We do not recognize a specific minimum fluid amount before starting vasopressor support.
          • i.
            Vasopressor support may be coupled with plasma volume expansion to prevent cardiovascular collapse in those with severe hypotension or life-threatening hypoperfusion without requiring that a fluid administration threshold be reached prior to vasopressor initiation.
        • We think serial examinations (using more than one bedside tool to assess the adequacy of resuscitation) are best, with no one approach demonstrated as superior to alternative approaches.
      • (2)
        We support using balanced crystalloid solutions (Ringer’s solution or Plasmalyte) as the primary resuscitation fluid in patients with sepsis, especially if volumes of more than 1 L are used.
        • Infusions of saline solution can cause hyperchloremic metabolic acidosis and may impair renal performance in commonly prescribed resuscitative doses.

       Fluid Volume and Concurrent Titration of Vasopressors

      Despite the widespread use of intravenous fluids for the management of sepsis, there remains controversy regarding the volume and rate of fluid administration.
      • Self W.H.
      • Semler M.W.
      • Bellomo R.
      • et al.
      Liberal versus restrictive intravenous fluid therapy for early septic shock: rationale for a randomized trial.
      For the past 2 decades, large mean volumes of intravenous fluid (eg, more than 3,000 to 5,000 mL) have been common in the care of ED patients with sepsis, especially those with septic shock.
      • Nguyen H.B.
      • Jaehne A.K.
      • Jayaprakash N.
      • et al.
      Early goal-directed therapy in severe sepsis and septic shock: insights and comparisons to ProCESS, ProMISe, and ARISE.
      Whereas intravenous fluid loading can optimize cardiac preload, recent data suggest that the effects of a fluid bolus on hemodynamics are often transient—an observation that may find some explanation in the well-described capillary leak observed with life-threatening infection.
      • Glassford N.J.
      • Eastwood G.M.
      • Bellomo R.
      Physiological changes after fluid bolus therapy in sepsis: a systematic review of contemporary data.
      ,
      • Nunes T.S.
      • Ladeira R.T.
      • Bafi A.T.
      • et al.
      Duration of hemodynamic effects of crystalloids in patients with circulatory shock after initial resuscitation.
      Recognition of secondary abdominal compartment syndrome and combined outcomes such as the major adverse kidney event assessment show that excessive fluid administration can worsen clinical outcomes.
      • Maitland K.
      • Kiguli S.
      • Opoka R.O.
      • et al.
      Mortality after fluid bolus in African children with severe infection.
      • Andrews B.
      • Semler M.W.
      • Muchemwa L.
      • et al.
      Effect of an early resuscitation protocol on in-hospital mortality among adults with sepsis and hypotension: a randomized clinical trial.
      • Marik P.E.
      • Linde-Zwirble W.T.
      • Bittner E.A.
      • et al.
      Fluid administration in severe sepsis and septic shock, patterns and outcomes: an analysis of a large national database.
      Determining how much fluid a given patient needs to abrogate hypovolemia remains a vexing issue. While doing so, one must vigilantly monitor for unintended fluid overload during resuscitation. Furthermore, certain clinical entities may degrade the elasticity of the cardiopulmonary system, as described during the SARS-CoV-2 pandemic, establishing additional concerns regarding fluid prescription titration.
      • Kazory A.
      • Ronco C.
      • McCullough P.A.
      SARS-CoV-2 (COVID-19) and intravascular volume management strategies in the critically ill.
      Many trials have used body mass‒based intravenous fluid dosing (20 or 30 mL/kg) to guide initial fluid resuscitation, but rigorous clinical trials of different volumes of intravenous fluids are challenging to conduct because of variations in comorbidities, time of presentation, and prevalence of obesity. Practical issues limit the feasibility of body mass‒based dosing, including poor estimates of body mass and unit doses of 500 mL and 1,000 mL, which make for natural break-points to assess for clinical response. Finally, patients with sepsis treated with the largest volumes of intravenous fluid in observational studies had less favorable outcomes. These observations raise questions of whether large and continued boluses of fluid improve clinical outcomes or are markers of severity of illness.
      • Marik P.E.
      • Linde-Zwirble W.T.
      • Bittner E.A.
      • et al.
      Fluid administration in severe sepsis and septic shock, patterns and outcomes: an analysis of a large national database.
      ,
      • Boyd J.H.
      • Forbes J.
      • Nakada T.
      • et al.
      Fluid resuscitation in septic shock: a positive fluid balance and elevated central venous pressure are associated with increased mortality.
      • Micek S.T.
      • McEvoy C.
      • McKenzie M.
      • et al.
      Fluid balance and cardiac function in septic shock as predictors of hospital mortality.
      • Acheampong A.
      • Vincent J.L.
      A positive fluid balance is an independent prognostic factor in patients with sepsis.
      • Sakr Y.
      • Rubatto Birri P.N.
      • Kotfis K.
      • et al.
      Higher fluid balance increases the risk of death from sepsis: results from a large international audit.
      Additionally, assessments of fluid administration are confounded by the indication for fluid delivery and the specific endpoints that were assessed.
      We do not believe data that support a singular body mass‒based volume for all or most patients, although we recognize that many will receive and respond to certain targets like 30 mL/kg. We believe any new guidelines should incorporate titration and response assessment along with defined aliquots, including body mass‒based, to optimally improve care. However, some patients will need more than the current guideline-suggested volume, whereas others may need a lesser volume or the same volume administered at a different rate. These different patient elements require bedside reevaluation during the course of resuscitation. Administration of an initial volume of 500 to 1,000 mL of crystalloid is a common and reasonable practice, as it affords the opportunity to gauge the patient’s response to the bolus, does not establish an endpoint for fluid therapy, and provides early insight into the need for concomitant vasopressor support.
      The assessment of fluid status and fluid responsiveness is commonly desired to guide care. Table 4 highlights methods currently available to help clinicians with volume status assessment.
      • Monnet X.
      • Marik P.
      • Teboul J.-L.
      Passive leg raising for predicting fluid responsiveness: a systematic review and meta-analysis.
      ,
      • Bentzer P.
      • Griesdale D.E.
      • Boyd J.
      • et al.
      Will this hemodynamically unstable patient respond to a bolus of intravenous fluids?.
      None of these methods is clearly superior to the others at improving sepsis survival; they are only some of the tools available to the bedside clinician to manage sepsis patients. In practice, using multiple tools to guide therapy is preferred, recognizing that the ability to collect some variables may differ across sites.
      Table 4Signs that can assist clinicians with evaluating patient volume status.
      Clinical Signs of HypoperfusionClinical Signs of Fluid Overload
      SBP <100 mm Hg (or less than baseline SBP for patients with baseline SBP <100 mm Hg)
      • Marchick M.R.
      • Kline J.A.
      • Jones A.E.
      The significance of non-sustained hypotension in emergency department patients with sepsis.
      Development of pulmonary crackles with fluid administration
      MAP <65 mm Hg (or less than baseline MAP for patients with baseline MAP <65 mm Hg)Increased jugular venous distention with fluid administration
      Heart pulse rate >110 beats/minIncreased work of breathing with fluid administration
      Shock index (pulse rate/SBP) >1.0Increased hypoxemia with fluid administration
      Elevated serum lactate levelsChest x-ray signs of pulmonary edema
      Peripheral capillary refill time >3 seconds
      • Hernández G.
      • Ospina-Tascón G.A.
      • Damiani L.P.
      • et al.
      Effect of a resuscitation strategy targeting peripheral perfusion status vs serum lactate levels on 28-day mortality among patients with septic shock: the ANDROMEDA-SHOCK randomized clinical trial.
      Ultrasound signs consistent with pulmonary edema (eg, B-lines)
      Depressed mental status
      Decreased urine output (<0.5 mL/kg per hour)
      In addition to simple volume assessment maneuvers, quantitative methods to predict which patients will respond favorably to a fluid bolus (“fluid responsiveness”) exist. These methods include measuring collapsibility of the inferior vena cava with bedside ultrasound, directly measuring stroke volume in response to a fluid bolus, and measuring the change in stroke volume or cardiac output in response to a passive leg raise (Table 4).
      • Monnet X.
      • Marik P.
      • Teboul J.-L.
      Passive leg raising for predicting fluid responsiveness: a systematic review and meta-analysis.
      • Bentzer P.
      • Griesdale D.E.
      • Boyd J.
      • et al.
      Will this hemodynamically unstable patient respond to a bolus of intravenous fluids?.
      • Muller L.
      • Bobbia X.
      • Toumi M.
      • et al.
      Respiratory variations of inferior vena cava diameter to predict fluid responsiveness in spontaneously breathing patients with acute circulatory failure: need for a cautious use.
      • Lanspa M.J.
      • Grissom C.K.
      • Hirshberg E.L.
      • et al.
      Applying dynamic parameters to predict hemodynamic response to volume expansion in spontaneously breathing patients with septic shock.
      • Latham H.E.
      • Bengtson C.D.
      • Satterwhite L.
      • et al.
      Stroke volume guided resuscitation in severe sepsis and septic shock improves outcomes.
      Although these methods are physiologically rational, clinical outcome data are insufficient at this time to support a recommendation for their use.

       Fluid Type

      The 2 major categories of resuscitation fluids are isotonic crystalloids and colloids (Figure 1).
      Figure thumbnail gr1
      Figure 1Major types of intravenous fluid available for resuscitation. We recommend balanced crystalloid solutions as the primary fluid type for resuscitation in sepsis. We do not recommend using colloids.
      Figure thumbnail gr2
      Figure 2Organizations involved in the development of the recommendations.
      Extravascular leakage of fluid is a physiologic hallmark of sepsis. Infusion of large volumes of crystalloid can contribute to extravascular leakage (edema), which potentially interferes with cellular function, including in the kidneys, liver, heart, and lungs.
      • Glassford N.J.
      • Eastwood G.M.
      • Bellomo R.
      Physiological changes after fluid bolus therapy in sepsis: a systematic review of contemporary data.
      ,
      • Maitland K.
      • George E.C.
      • Evans J.A.
      • et al.
      Exploring mechanisms of excess mortality with early fluid resuscitation: insights from the FEAST trial.
      ,
      • Marik P.E.
      Iatrogenic salt water drowning and the hazards of a high central venous pressure.
      The use of colloids is based on the theory that higher-weight molecules limit extravascular leakage and increase long-term intravascular volume.
      • Myburgh J.A.
      • Mythen M.G.
      Resuscitation fluids.
      Colloids have properties that potentially make them a better choice for sepsis resuscitation than crystalloids, but sepsis physiology leads to increased capillary permeability, limiting the physiologic benefit in disease. Clinical outcome data have not consistently demonstrated the superiority of colloids over crystalloids.
      • Perner A.
      • Haase N.
      • Guttormsen A.B.
      • et al.
      Hydroxyethyl starch 130/0.42 versus Ringer’s acetate in severe sepsis.
      • Caironi P.
      • Tognoni G.
      • Masson S.
      • et al.
      Albumin replacement in patients with severe sepsis or septic shock.
      • Finfer S.
      • Bellomo R.
      • Boyce N.
      • et al.
      A comparison of albumin and saline for fluid resuscitation in the intensive care unit.
      • Jiang L.
      • Jiang S.
      • Zhang M.
      • et al.
      Albumin versus other fluids for fluid resuscitation in patients with sepsis: a meta-analysis.
      We agree that the lack of established benefits and the higher cost of colloids support crystalloid solutions over colloids for initial volume expansion in sepsis.
      Among crystalloids, the primary choices are saline solution (0.9% sodium chloride, or “normal saline”) and balanced crystalloids.
      • Myburgh J.A.
      • Mythen M.G.
      Resuscitation fluids.
      Saline solution contains a supraphysiologic concentration of chloride (154 mmol/L), which can lead to hyperchloremic metabolic acidosis and may increase renal inflammation and impair renal perfusion.
      • Wilcox C.S.
      Regulation of renal blood flow by plasma chloride.
      ,
      • Zhou F.
      • Peng Z.Y.
      • Bishop J.V.
      • et al.
      Effects of fluid resuscitation with 0.9% saline versus a balanced electrolyte solution on acute kidney injury in a rat model of sepsis∗.
      Balanced crystalloids have a higher physiologic electrolyte composition and include lactated Ringer’s solution (chloride concentration 109 mmol/L), Plasmalyte (chloride concentration 98 mmol/L), and Normosol-R (chloride concentration 98 mmol/L).
      • Myburgh J.A.
      • Mythen M.G.
      Resuscitation fluids.
      Recent data suggest that fluid resuscitation with balanced crystalloids leads to improved patient outcomes compared with saline solution among a general ED population, those who are critically ill, and those with sepsis.
      • Self W.H.
      • Semler M.W.
      • Wanderer J.P.
      • et al.
      Balanced crystalloids versus saline in noncritically ill adults.
      • Semler M.W.
      • Self W.H.
      • Wanderer J.P.
      • et al.
      Balanced crystalloids versus saline in critically ill adults.
      • Brown R.M.
      • Wang L.
      • Coston T.D.
      • et al.
      Balanced crystalloids versus saline in sepsis: a secondary analysis of the SMART clinical trial.
      Data supporting sepsis patient resuscitation using balanced crystalloids over saline solution are largely based on single-center trials.
      • Self W.H.
      • Semler M.W.
      • Wanderer J.P.
      • et al.
      Balanced crystalloids versus saline in noncritically ill adults.
      • Semler M.W.
      • Self W.H.
      • Wanderer J.P.
      • et al.
      Balanced crystalloids versus saline in critically ill adults.
      • Brown R.M.
      • Wang L.
      • Coston T.D.
      • et al.
      Balanced crystalloids versus saline in sepsis: a secondary analysis of the SMART clinical trial.
      The results of ongoing multicenter trials will more fully characterize the comparative effects of balanced crystalloids and saline solution, but we believe that current evidence coupled with known risks of saline solution are sufficient to favor the use of balanced crystalloids for those with sepsis.
      • Young P.J.
      Balanced crystalloids or 0.9% saline in sepsis: beyond reasonable doubt?.

       Vasopressors

      Key Points:
      • (1)
        Norepinephrine is an excellent first-line vasopressor for patients with septic shock.
      • (2)
        Titrating vasopressors to maintain a MAP of at least 65 mm Hg in most patients is a common target.
      • (3)
        Early vasopressors can be administered through a well-secured nondistal peripheral IV catheter.
      Norepinephrine is the preferred first-line agent for patients with septic shock.
      • Avni T.
      • Lador A.
      • Lev S.
      • et al.
      Vasopressors for the treatment of septic shock: systematic review and meta-analysis.
      ,
      • Russell J.A.
      • Walley K.R.
      • Singer J.
      • et al.
      Vasopressin versus norepinephrine infusion in patients with septic shock.
      Adding vasopressin (0.03 to 0.04 U/min) is a reasonable approach to reduce norepinephrine requirements and decrease complications, especially at high doses.
      • Russell J.A.
      • Walley K.R.
      • Singer J.
      • et al.
      Vasopressin versus norepinephrine infusion in patients with septic shock.
      ,
      • McIntyre W.F.
      • Um K.J.
      • Alhazzani W.
      • et al.
      Association of vasopressin plus catecholamine vasopressors vs catecholamines alone with atrial fibrillation in patients with distributive shock: a systematic review and meta-analysis.
      In patients with ongoing hypotension despite high doses of norepinephrine, or in patients with echocardiographic evidence of myocardial depression, epinephrine is a second-line vasopressor and inotropic agent.
      • Annane D.
      • Vignon P.
      • Renault A.
      • et al.
      Norepinephrine plus dobutamine versus epinephrine alone for management of septic shock: a randomised trial.
      ,
      • Myburgh J.A.
      • Higgins A.
      • Jovanovska A.
      • et al.
      A comparison of epinephrine and norepinephrine in critically ill patients.
      We recommend titrating vasopressors to maintain a MAP of at least 65 mm Hg unless the patient has baseline hypertension and evidence of hypoperfusion with a MAP of more than 65.
      • Asfar P.
      • Meziani F.
      • Hamel J.-F.
      • et al.
      High versus low blood-pressure target in patients with septic shock.
      ,
      • Lamontagne F.
      • Meade M.O.
      • Hébert P.C.
      • et al.
      Higher versus lower blood pressure targets for vasopressor therapy in shock: a multicentre pilot randomized controlled trial.
      Consider titration of vasopressors to achieve improvement in markers of organ perfusion (urine output, lactate) as an approach to management of patients with baseline hypertension.
      Central venous access was historically required before initiating vasopressor therapy in many sites. This practice affects early sepsis care by delaying the initiation of vasopressor infusion therapy, which may increase large-volume fluid administration while awaiting catheter placement, evaluation, and clearance for use. Current limited data suggest that early administration of peripheral norepinephrine through large-bore peripheral intravenous catheters for short intervals with appropriate monitoring is safe during resuscitation.
      • Permpikul C.
      • Tongyoo S.
      • Viarasilpa T.
      • et al.
      Early use of norepinephrine in septic shock resuscitation (CENSER). A randomized trial.
      • Cardenas-Garcia J.
      • Schaub K.F.
      • Belchikov Y.G.
      • et al.
      Safety of peripheral intravenous administration of vasoactive medication.
      • Loubani O.M.
      • Green R.S.
      A systematic review of extravasation and local tissue injury from administration of vasopressors through peripheral intravenous catheters and central venous catheters.
      • Lewis T.
      • Merchan C.
      • Altshuler D.
      • et al.
      Safety of the peripheral administration of vasopressor agents.
      • Delaney A.
      • Finnis M.
      • Bellomo R.
      • et al.
      Initiation of vasopressor infusions via peripheral versus central access in patients with early septic shock: a retrospective cohort study.

       Antimicrobials

      Key Points:
      • (1)
        We support early antibiotics once sepsis is diagnosed or deemed likely. The strongest support for initial intravenous antibiotics is in those with suspected diagnosis of septic shock—that is, patients with infection and any hypotension or hypoperfusion.
        • Shorter time to antibiotics is preferred, but the precise time frame to optimally support outcomes remains to be defined.
        • Emerging data will help address the impact of the timing of subsequent doses, especially for patients who remain in the ED due to the lack of an appropriate inpatient bed.
        • Antivirals are less clearly time sensitive in the earliest phases of disease.
      • (2)
        For sepsis patients without an identified pathogen, we recommend initiation of broad-spectrum antibiotics with activity against gram-negative and gram-positive bacteria according to local susceptibility patterns.

       Antimicrobials: General Principles

      Most sepsis patients receive initial doses of antimicrobials in the ED prior to the availability of culture results. In general, clinicians should base the initial selection of antimicrobials on the most likely and most harmful potential pathogens rather than targeting a specific pathogen, unless the clinical presentation directs such a focused approach. Narrow-spectrum therapy is uncommon and should not be anticipated in usual practice. Clinicians should treat patients with broad-spectrum antibacterial agents. Specific patients may require additional coverage for influenza or fungal infections, both of which have been characterized in guidelines or consensus documents; this may be further informed and adjusted by local patient population‒appropriate antibiogram data.
      • Uyeki T.M.
      • Bernstein H.H.
      • Bradley J.S.
      • et al.
      Clinical practice guidelines by the Infectious Diseases Society of America: 2018 update on diagnosis, treatment, chemoprophylaxis, and institutional outbreak management of seasonal influenza.
      ,
      • Tunkel A.R.
      • Hartman B.J.
      • Kaplan S.L.
      • et al.
      Practice guidelines for the management of bacterial meningitis.
      • Pappas P.G.
      • Kauffman C.A.
      • Andes D.R.
      • et al.
      Clinical practice guideline for the management of candidiasis: 2016 update by the Infectious Diseases Society of America.
      • Hooton T.M.
      • Bradley S.F.
      • Cardenas D.D.
      • et al.
      Diagnosis, prevention, and treatment of catheter-associated urinary tract infection in adults: 2009 international clinical practice guidelines from the Infectious Diseases Society of America.
      • Metlay J.P.
      • Waterer G.W.
      • Long A.C.
      • et al.
      Diagnosis and treatment of adults with community-acquired pneumonia. An official clinical practice guideline of the American Thoracic Society and Infectious Diseases Society of America.
      • Lipsky B.A.
      • Berendt A.R.
      • Cornia P.B.
      • et al.
      2012 Infectious Diseases Society of America clinical practice guideline for the diagnosis and treatment of diabetic foot infections.
      • Baddour L.M.
      • Wilson W.R.
      • Bayer A.S.
      • et al.
      Infective endocarditis in adults: diagnosis, antimicrobial therapy, and management of complications: a scientific statement for healthcare professionals from the American Heart Association.
      • Solomkin J.S.
      • Mazuski J.E.
      • Bradley J.S.
      • et al.
      Diagnosis and management of complicated intra-abdominal infection in adults and children: guidelines by the Surgical Infection Society and the Infectious Diseases Society of America.
      • Liu C.
      • Bayer A.
      • Cosgrove S.E.
      • et al.
      Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children.
      • Stevens D.L.
      • Bisno A.L.
      • Chambers H.F.
      • et al.
      Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 update by the Infectious Diseases Society of America.
      • Gupta K.
      • Hooton T.M.
      • Naber K.G.
      • et al.
      International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: A 2010 update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases.

       Timing of Antibiotics

      Whereas some data suggest that an earlier administration of antibiotics is associated with better survival,
      • Seymour C.W.
      • Gesten F.
      • Prescott H.C.
      • et al.
      Time to treatment and mortality during mandated emergency care for sepsis.
      ,
      • Kumar A.
      • Roberts D.
      • Wood K.E.
      • et al.
      Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock.
      • Ferrer R.
      • Martin-Loeches I.
      • Phillips G.
      • et al.
      Empiric antibiotic treatment reduces mortality in severe sepsis and septic shock from the first hour: results from a guideline-based performance improvement program.
      door-to-antibiotic time and long-term mortality in sepsis.
      • Liu V.X.
      • Fielding-Singh V.
      • Greene J.D.
      • et al.
      The timing of early antibiotics and hospital mortality in sepsis.
      other data suggest that small variations in the timing of a first dose of antibiotics are not associated with mortality differences.
      • Alam N.
      • Oskam E.
      • Stassen P.M.
      • et al.
      Prehospital antibiotics in the ambulance for sepsis: a multicentre, open label, randomized trial.
      ,
      • Sterling S.A.
      • Miller W.R.
      • Pryor J.
      • et al.
      The impact of timing of antibiotics on outcomes in severe sepsis and septic shock: a systematic review and meta-analysis.
      ,
      • Hranjec T.
      • Rosenberger L.H.
      • Swenson B.
      • et al.
      Aggressive versus conservative initiation of antimicrobial treatment in critically ill surgical patients with suspected intensive-care-unit-acquired infection: a quasi-experimental, before and after observational cohort study.
      Guidelines often outline time-based approaches to drive earlier action—for example, the Surviving Sepsis Campaign that included the administration of antibiotics by the first hour. We agree that once the diagnosis of sepsis is established, rapid and comprehensive therapy—not just antibiotic administration—is optimal. But the current data do not recommend a singular time target that clearly improves outcomes for all. In those with the most severe form of sepsis—septic shock—the data and collective experience support a shorter time window; otherwise, the relationship between time and outcome is less clear.
      • Rhee C.
      • Strich J.R.
      • Klompas M.
      • et al.
      SEP-1 has brought much needed attention to improving sepsis care…but now is the time to improve SEP-1.
      ,
      • Weinberger J.
      • Rhee C.
      • Klompas M.
      A critical analysis of the literature on time-to-antibiotics in suspected sepsis.

       Viruses

      Viral infections, such as those caused by influenza and SARS-CoV-2, can cause sepsis. Specific treatment recommendations for these viral infections are beyond the scope of this effort. Antiviral therapy can be initiated in the ED, although no timing threshold data exist.

       Fungi

      Fungi can trigger sepsis, and the most common cause of fungal sepsis is Candida. Risk factors for invasive Candida infection include prior invasive Candida infection, current Candida colonization, total parenteral nutrition, recent major abdominal surgery, recent exposure to broad-spectrum antibiotics, recent prolonged hospitalization, acute necrotizing pancreatitis, neutropenia, chronic corticosteroid use, and chronic indwelling vascular catheters.
      • Pappas P.G.
      • Kauffman C.A.
      • Andes D.R.
      • et al.
      Clinical practice guideline for the management of candidiasis: 2016 update by the Infectious Diseases Society of America.
      In patients at high risk of fungal sepsis, antifungal therapy with activity for likely pathogens should be initiated in the ED.
      • Garey K.W.
      • Rege M.
      • Pai M.P.
      • et al.
      Time to initiation of fluconazole therapy impacts mortality in patients with candidemia: a multi-institutional study.
      ,
      • Morrell M.
      • Fraser V.J.
      • Kollef M.H.
      Delaying the empiric treatment of candida bloodstream infection until positive blood culture results are obtained: a potential risk factor for hospital mortality.

       Infection Source Control

      Key Points:
      • (1)
        We support early identification of infections requiring source control, and we recommend early consultation and procedural intervention to control infection sources.
      • (2)
        No specific timing threshold for achieving source control currently exists.
      When infections are suspected that have an easily removable source (eg, indwelling vascular access catheter, soft tissue abscess), early action is appropriate. Focal sources of infection should prompt consultation by procedural specialists for source control, including tunneled vascular catheters, hemodialysis lines, vascular ports, implanted devices, infected ureteral stones, biliary ductal obstruction with cholangitis, deep space or body cavity abscesses, intestinal perforation or obstruction with ischemia, necrotizing soft tissue infection, and complications of infections such as those related to Clostridium difficile colitis.
      • Jimenez M.F.
      • Marshall J.C.
      International Sepsis Forum
      Source control in the management of sepsis.
      Source control should not delay the initiation of resuscitation or antibiotics; resuscitation and source control often need to occur concurrently.

      Titration of Care

      Titration of care—that is, delivering ongoing fluids, vasopressor, respiratory support, or other interventions based on the individual response to the first care steps—is relevant to emergency care providers, especially when sepsis patients board in the ED awaiting inpatient bed availability or interfacility transfer.

       Ongoing Fluid Administration

      Key Points:
      • (1)
        Fluid administration after an initial bolus should be based on serial assessments of the patient and response to therapy.
      • (2)
        No singular assessment approach is superior, and we recommend using multiple assessments, including basic vital signs and physical examination methods (a clinical evaluation) or more advanced physiologic measurements (quantitative evaluation) at multiple time intervals.
      • (3)
        If using a quantitative resuscitation approach, we recommend dynamic measures over static measures.
      Up to 50% of patients with septic shock fail to increase cardiac output in response to fluid administration, and when fluid loading does lead to increased cardiac output, the response is often transient.
      • Glassford N.J.
      • Eastwood G.M.
      • Bellomo R.
      Physiological changes after fluid bolus therapy in sepsis: a systematic review of contemporary data.
      ,
      • Monnet X.
      • Marik P.
      • Teboul J.-L.
      Passive leg raising for predicting fluid responsiveness: a systematic review and meta-analysis.
      ,
      • Michard F.
      • Teboul J.L.
      Predicting fluid responsiveness in ICU patients: a critical analysis of the evidence.
      • Lanspa M.J.
      • Brown S.M.
      • Hirshberg E.L.
      • et al.
      Central venous pressure and shock index predict lack of hemodynamic response to volume expansion in septic shock: a prospective, observational study.
      • Osman D.
      • Ridel C.
      • Ray P.
      • et al.
      Cardiac filling pressures are not appropriate to predict hemodynamic response to volume challenge.
      • Marik P.E.
      • Cavallazzi R.
      • Vasu T.
      • et al.
      Dynamic changes in arterial waveform derived variables and fluid responsiveness in mechanically ventilated patients: a systematic review of the literature.
      Identifying patients who respond to fluids is one way to tailor an appropriate volume of fluid administration. Septic shock can manifest as a combination of preload-dependent, distributive, and cardiogenic shock, and all patients with ongoing hypotension or elevated lactate levels after initial fluid resuscitation need repeated hemodynamic assessment.
      Because no specific method of hemodynamic assessment in treating sepsis patients is clearly superior in altering survival, we present 2 approaches: (1) a clinical evaluation, which focuses on basic assessment techniques that are widely available in emergency care settings; and (2) a quantitative evaluation, which uses more advanced assessment methods with equipment and expertise that may not be available in all emergency care settings. Both clinical and quantitative evaluations are reasonable approaches for monitoring and serial assessment. Using either method, a key principle is that sepsis assessment should iteratively use multiple parameters to guide therapy.

       Clinical Evaluation

      The clinical evaluation uses changes in vital signs and the physical examination to assess response to care. Although vital signs (eg, blood pressure and heart rate) and physical examination findings are poorly sensitive markers when taken alone, changes in these parameters are often important indicators to guide therapy. Patients who improve with the initial bolus of fluid are candidates for subsequent fluid boluses, using aliquots (such as 500 to 1,000 mL) followed by repeat serial clinical examinations to evaluate response to fluid administration and evidence of volume overload (Table 4). Clinicians may assess peripheral perfusion (eg, capillary refill), which, in one trial, performed similarly to lactate clearance in identifying adequacy of fluid resuscitation and selecting fluid resuscitation volumes.
      • Hernández G.
      • Ospina-Tascón G.A.
      • Damiani L.P.
      • et al.
      Effect of a resuscitation strategy targeting peripheral perfusion status vs serum lactate levels on 28-day mortality among patients with septic shock: the ANDROMEDA-SHOCK randomized clinical trial.
      Urine output is another tool to assess ongoing resuscitation success, but it is not helpful for the common shorter ED care intervals and is eased by indwelling catheter use, the latter sometimes avoided to lessen iatrogenic infections.
      • Peerapornratana S.
      • Manrique-Caballero
      • Gómez H.
      • et al.
      Acute kidney injury from sepsis: current concepts, epidemiology, pathophysiology, prevention and treatment.

       Quantitative Evaluation

      Quantitative measures of cardiovascular function assess physiologic changes in response to fluid administration. Current data do not support improved survival with any specific quantitative evaluation, but quantitative methods add insight to those titrating shock therapy. The term “quantitative evaluation” encompasses both static and dynamic measures of volume status. Static measures (eg, central venous pressure) are typically pressures or volumes measured in isolation, whereas dynamic measures evaluate physiologic changes in response to a fluid bolus, passive leg raise, or respiratory variation. We recommend using dynamic measures over static measures because dynamic measures are stronger predictors of a patient’s clinical response to fluid administration.
      • Bednarczyk J.M.
      • Fridfinnson J.A.
      • Kumar A.
      • et al.
      Incorporating dynamic assessment of fluid responsiveness into goal-directed therapy: a systematic review and meta-analysis.
      Many dynamic measures exist, including pulse pressure variation, stroke volume variation, passive leg raise measurement with continuous stroke volume or cardiac output measurement, inferior vena cava collapsibility on ultrasound, and the aortic valve velocity time integral.
      • Monnet X.
      • Marik P.
      • Teboul J.-L.
      Passive leg raising for predicting fluid responsiveness: a systematic review and meta-analysis.
      ,
      • Bentzer P.
      • Griesdale D.E.
      • Boyd J.
      • et al.
      Will this hemodynamically unstable patient respond to a bolus of intravenous fluids?.
      ,
      • Yang X.
      • Du B.
      Does pulse pressure variation predict fluid responsiveness in critically ill patients? A systematic review and meta-analysis.
      • Cherpanath T.G.
      • Hirsch A.
      • Geerts B.F.
      • et al.
      Predicting fluid responsiveness by passive leg raising: a systematic review and meta-analysis of 23 clinical trials.
      • Joosten A.
      • Desebbe O.
      • Suehiro K.
      • et al.
      Accuracy and precision of non-invasive cardiac output monitoring devices in perioperative medicine: a systematic review and meta-analysis.
      • Zhang Z.
      • Xu X.
      • Ye S.
      • et al.
      Ultrasonographic measurement of the respiratory variation in the inferior vena cava diameter is predictive of fluid responsiveness in critically ill patients: systematic review and meta-analysis.
      • Huang H.
      • Shen Q.
      • Liu Y.
      • et al.
      Value of variation index of inferior vena cava diameter in predicting fluid responsiveness in patients with circulatory shock receiving mechanical ventilation: a systematic review and meta-analysis.
      • Orso D.
      • Paoli I.
      • Piani T.
      • et al.
      Accuracy of ultrasonographic measurements of inferior vena cava to determine fluid responsiveness: a systematic review and meta-analysis.
      At this time, no data exist to demonstrate that assessment or care provision on the basis of specific dynamic measures are associated with survival more than others.

       Vascular Access and Invasive Monitoring

      Key Points:
      • (1)
        Vasopressor administration through peripheral intravenous or intraosseous catheters that are monitored for signs of good functioning is acceptable for short-term use.
      • (2)
        Invasive hemodynamic devices, including central venous and arterial catheters, may aid but are not routinely needed in early sepsis care.
      Septic shock patients may have vasopressor therapy initiated through large, well-functioning peripheral intravenous catheters or intraosseous catheters without delay for central venous access. Monitor peripheral catheters used for vasopressor therapy frequently for signs of malfunction or extravasation and obtain central venous access if access challenges exist or if prolonged therapy is anticipated.
      • Cardenas-Garcia J.
      • Schaub K.F.
      • Belchikov Y.G.
      • et al.
      Safety of peripheral intravenous administration of vasoactive medication.
      ,
      • Loubani O.M.
      • Green R.S.
      A systematic review of extravasation and local tissue injury from administration of vasopressors through peripheral intravenous catheters and central venous catheters.
      ,
      • Medlej K.
      • Kazzi A.A.
      • El Hajj Chehade A.
      • et al.
      Complications from administration of vasopressors through peripheral venous catheters: an observational study.
      During the early period of resuscitation, noninvasive blood pressure measurement is reasonable, especially if blood pressure normalizes with fluid or vasopressor administration.
      • Wax D.B.
      • Lin H.M.
      • Leibowitz A.B.
      Invasive and concomitant noninvasive intraoperative blood pressure monitoring: observed differences in measurements and associated therapeutic interventions.
      • Ribezzo S.
      • Spina E.
      • Di Bartolomeo S.
      • et al.
      Noninvasive techniques for blood pressure measurement are not a reliable alternative to direct measurement: a randomized crossover trial in ICU.
      • Riley L.E.
      • Chen G.J.
      • Latham H.E.
      Comparison of noninvasive blood pressure monitoring with invasive arterial pressure monitoring in medical ICU patients with septic shock.
      • Lakhal K.
      • Macq C.
      • Ehrmann S.
      • et al.
      Noninvasive monitoring of blood pressure in the critically ill: reliability according to the cuff site (arm, thigh, or ankle).
      Patients with poor or unreliable blood pressure measurements by noninvasive blood pressure cuffs may benefit from arterial catheter placement for blood pressure monitoring and titration of therapy.

       Subsequent Doses of Antibiotics

      Key Points:
      • (1)
        Patients who remain in the ED for prolonged periods should have subsequent doses of antibiotics administered according to the optimal dosing schedule for each medication.
      For patients remaining in the ED for prolonged periods, second and subsequent doses of antibiotics are important to optimize the antimicrobial effect. These doses must be scheduled and administered regardless of where the patient is located. Delays in follow-up antibiotics are associated with worse outcomes, and EDs must ensure safe transitions and ongoing dosing.
      • Leisman D.
      • Huang V.
      • Zhou Q.
      • et al.
      Delayed second dose antibiotics for patients admitted from the emergency department with sepsis: prevalence, risk factors, and outcomes.

       Adjunctive Early Sepsis Therapies

      Key Points:
      • (1)
        Routine corticosteroid therapy does not benefit sepsis patients unless there is concomitant adrenal insufficiency or the patient is on high-dose corticosteroid therapy for comorbid disease management prior to the onset of sepsis.
      • (2)
        Other adjuncts, including angiotensin II (or analogs), vitamin C, vitamin D, and thiamine—alone or in combination—lack strong evidence supporting benefit and are not recommended.
      Patients with sepsis who have been chronically taking corticosteroid therapy
      • Broersen L.H.
      • Pereira A.M.
      • Jørgensen J.O.L.
      • et al.
      Adrenal insufficiency in corticosteroids use: systematic review and meta-analysis.
      or who have preexisting adrenal insufficiency should receive stress-dose hydrocortisone (50 to 100 mg intravenously). However, outside selected sepsis patients, routine corticosteroid use has been controversial. An early randomized trial showed improved survival in patients with poor adrenal response (“relative adrenal insufficiency”) and very high illness severity.
      • Annane D.
      • Sebille V.
      • Charpentier C.
      • et al.
      Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock.
      Subsequent trials have shown varying results, with the most recent evidence suggesting that corticosteroid therapy may speed resolution of shock and shorten intensive care unit and hospital length of stay. Recent meta-analyses have come to varying conclusions on the impact of steroids on mortality, and some now recommend their use.
      • Sprung C.L.
      • Annane D.
      • Keh D.
      • et al.
      Hydrocortisone therapy for patients with septic shock.
      • Annane D.
      • Bellissant E.
      • Bollaert P.E.
      • et al.
      Corticosteroids for treating sepsis.
      • Rochwerg B.
      • Oczkowski S.J.
      • Siemieniuk R.A.C.
      • et al.
      Corticosteroids in sepsis: an updated systematic review and meta-analysis.
      • Lamontagne F.
      • Rochwerg B.
      • Lytvyn L.
      • et al.
      Corticosteroid therapy for sepsis: a clinical practice guideline.
      • Annane D.
      • Renault A.
      • Brun-Buisson C.
      • et al.
      Hydrocortisone plus fludrocortisone for adults with septic shock.
      • Venkatesh B.
      • Finfer S.
      • Cohen J.
      • et al.
      Adjunctive glucocorticoid therapy in patients with septic shock.
      • Fang F.
      • Zhang Y.
      • Tang J.
      • et al.
      Association of corticosteroids treatment with outcomes in adult patients with sepsis: a systematic review and meta-analysis.
      • Yao Y.Y.
      • Lin L.L.
      • Gu H.Y.
      • et al.
      Are corticosteroids beneficial for sepsis and septic shock? Based on pooling analysis of 16 studies.
      We believe that steroids may play a role in patients with hypotension resistant to vasopressor therapy, but that is uncertain; otherwise, the current data do not support routine use outside of adrenal failure or suppression or to treat another condition (eg, immune-modulated respiratory failure).
      Other sepsis adjuncts, such as combination therapy with vitamin C, thiamine, and hydrocortisone, as well as novel therapeutics such as angiotensin II, have insufficient evidence to support incorporation into routine ED practice.
      • Marik P.E.
      • Linde-Zwirble W.T.
      • Bittner E.A.
      • et al.
      Fluid administration in severe sepsis and septic shock, patterns and outcomes: an analysis of a large national database.
      ,
      • Khanna A.
      • English S.W.
      • Wang X.S.
      • et al.
      Angiotensin II for the treatment of vasodilatory shock.
      • Fowler 3rd, A.A.
      • Truwit J.D.
      • Hite R.D.
      • et al.
      Effect of vitamin C infusion on organ failure and biomarkers of inflammation and vascular injury in patients with sepsis and severe acute respiratory failure: the CITRIS-ALI randomized clinical trial.
      • Fujii T.
      • Luethi N.
      • Young P.J.
      • et al.
      Effect of vitamin C, hydrocortisone, and thiamine vs hydrocortisone alone on time alive and free of vasopressor support among patients with septic shock: the VITAMINS randomized clinical trial.

       Role of Interhospital Transfer, Inpatient Boarding, and Care Transitions in Sepsis Management

      Key Points:
      • (1)
        ED boarding (defined as prolonged care awaiting inpatient transfer) presents additional risk for sepsis patients. If local facilities do not have the capabilities to promptly care for critically ill patients, we recommend transfer of sepsis patients from the initial ED to an accepting facility with capabilities for managing these patients.
      • (2)
        Each institution should develop a plan that defines explicit accountability for sepsis patients receiving prolonged ED care.
      Some facilities do not have the capability to manage patients with complex infections or organ failure syndromes.
      • Gaieski D.F.
      • Edwards J.M.
      • Kallan M.J.
      • et al.
      The relationship between hospital volume and mortality in severe sepsis.
      ,
      • Kocher K.E.
      • Haggins A.N.
      • Sabbatini A.K.
      • et al.
      Emergency department hospitalization volume and mortality in the United States.
      In those centers, prompt recognition and identification for interhospital transfer is important and may parallel existing injury‒related care transfer approaches. Because of the importance of early antimicrobial therapy and resuscitation, delivery of antibiotics, IV fluids, and vasopressors should be started prior to transfer, as noted earlier. Some high-performing regional sepsis networks include collaboration with referral centers, providing feedback about patient outcomes, and screening for subsequent inpatient transfers.
      Inpatient boarding (eg, prolonged ED care while awaiting inpatient bed availability) is linked to increased mortality in observational studies of patients with severe infection.
      door-to-antibiotic time and long-term mortality in sepsis.
      ,
      • Chalfin D.B.
      • Trzeciak S.
      • Likourezos A.
      • et al.
      Impact of delayed transfer of critically ill patients from the emergency department to the intensive care unit.
      • Al-Qahtani S.
      • Alsultan A.
      • Haddad S.
      • et al.
      The association of duration of boarding in the emergency room and the outcome of patients admitted to the intensive care unit.
      • Zhang Z.
      • Bokhari F.
      • Guo Y.
      • et al.
      Prolonged length of stay in the emergency department and increased risk of hospital mortality in patients with sepsis requiring ICU admission.
      • Gaieski D.F.
      • Agarwal A.K.
      • Mikkelsen M.E.
      • et al.
      The impact of ED crowding on early interventions and mortality in patients with severe sepsis.
      • Guttmann A.
      • Schull M.J.
      • Vermeulen M.J.
      • et al.
      Association between waiting times and short term mortality and hospital admission after departure from emergency department: population based cohort study from Ontario, Canada.
      • Morley C.
      • Unwin M.
      • Peterson G.M.
      • et al.
      Emergency department crowding: a systematic review of causes, consequences and solutions.
      • Singer A.J.
      • Thode Jr., H.C.
      • Viccellio P.
      • et al.
      The association between length of emergency department boarding and mortality.
      Hypothesized reasons for worse outcomes include delayed administration of subsequent doses of antibiotics, limited monitoring resulting in delayed recognition of changes in patient status, high patient-to-nurse ratios, and provider focus on new patient evaluation.
      • Gaieski D.F.
      • Agarwal A.K.
      • Mikkelsen M.E.
      • et al.
      The impact of ED crowding on early interventions and mortality in patients with severe sepsis.
      ,
      • Mohr N.M.
      • Wessman B.T.
      • Bassin B.
      • et al.
      Boarding of critically ill patients in the emergency department.
      To optimize outcomes, we advise prioritizing septic shock patients for early inpatient bed availability owing to increased resource and time demands in care management. Furthermore, hospitals should develop systems to provide the necessary care for patients with sepsis who remain in an ED while awaiting an inpatient bed.
      • Mohr N.M.
      • Wessman B.T.
      • Bassin B.
      • et al.
      Boarding of critically ill patients in the emergency department.
      During periods of boarding, some facilities incorporate procedures whereby inpatient physician or nurse teams assume care of admitted patients in the ED. These procedures should be clearly delineated so that all members of the care team understand who is responsible and accountable for care. Other facilities have dedicated spaces for critical care management, whereas others, as noted earlier, have dedicated spaces, teams, and supplies. During transitions of care between hospitals, treatment units, or providers, we recommend timely provider-to-provider and nurse-to-nurse communication and the use of standardized care transition protocols.

      Related Controversies

      Key Points:
      • (1)
        We support recommendations and quality assessment tools required by government or regulatory bodies as important ways to improve the outcomes of those with sepsis, and we believe these should be based on the best available evidence and should undergo regular reevaluation.
      • (2)
        The creation of recommendations, guidelines, and quality assessment tools must include input from all relevant stakeholders engaged at each phase of care and must incorporate assessment of impact on both targeted patients and others receiving care.

       Quality Metrics

      Guidelines for sepsis care include standardized recommendations, such as the Severe Sepsis and Septic Shock (SEP-1) quality reporting measure within the National Hospital Inpatient Quality Reporting program
      Hospital Inpatient Specifications Manuals. United States Department of Health & Human Services, Centers for Medicare & Medicaid Services.
      and the Surviving Sepsis Campaign Guidelines. We recognize that these and other efforts raise awareness and performance and potentially improve outcomes. It is also important to recognize that some clinical realities trigger situation-dependent decisionmaking that is requisite for management of the ED sepsis patient. Instead, those decisions may reflect unique patient physiology or response to therapy that requires rapid readjustment. When faced with such clinical challenges, bedside clinicians should not be penalized for responding to patient response to therapy.
      When seeking to improve sepsis care, the input of experts with emergency care backgrounds is essential, alongside that of other experts, to ensure that the important early steps align with the knowledge and capabilities of the emergency care system. Those creating recommendations, guidelines, or quality metrics should reach to this pool of partners to optimize the applicability of what is considered optimal and feasible care.

       Sepsis Care in Constrained Settings

      We focused on care settings with advanced emergency and critical care medicine capabilities, including close hemodynamic monitoring, administration of vasopressors, and mechanical ventilation. We recognize that resource-constrained settings place practical limitations on the care options available; care must be modified in those settings. For example, recent clinical trials in settings where different patient and pathogen patterns existed and where advanced critical care capabilities were uncommon suggested that lower volumes of intravenous fluid administration may lead to better patient outcomes.
      • Maitland K.
      • Kiguli S.
      • Opoka R.O.
      • et al.
      Mortality after fluid bolus in African children with severe infection.
      ,
      • Andrews B.
      • Semler M.W.
      • Muchemwa L.
      • et al.
      Effect of an early resuscitation protocol on in-hospital mortality among adults with sepsis and hypotension: a randomized clinical trial.
      Sepsis remains a leading cause of death in the world, especially in the very young and very old and in resource-limited settings. Improving care in these settings must be distinct in composition from that in highly resourced hospitals in the United States.
      In conclusion, our multidisciplinary task force identified opportunities to improve recommendations, guidance, and quality metrics for early sepsis care. The points reviewed and suggested within this document seek to foster the next set of improvements for a leading cause of mortality. We identified many specific content and process opportunities in which research and collaboration could advance care, health, and outcomes. These include clear opportunities to guide fluid, vasopressor, and antibiotic therapy and thoughts on ancillary care and future guideline development. Optimal future sepsis recommendations will rely on a collaborative multiple stakeholder engagement approach to evaluating current processes, designing iterative improvements, and discovering new knowledge in the quest to conquer sepsis.
      Members of the American College of Emergency Physicians Multispecialty Sepsis Review Panel reviewed the drafts after initial composition and offered input: Jennifer Alexband, DO, Michael Benham, MD, David A. Farcy, MD, Marianne Gausche-Hill, MD, Sean Hickey, MD, Ryan C. Jacobsen, MD, Chadwick Miller, MD, Michael Puskarich, MD, Chanu Rhee, MD, MPH, Lisa Shieh, MD, PhD, Elizabeth Tedesco, DNP, RN, CEN, PHRN, Julie Winkle Mayglothling, MD, Christopher Zabbo, DO, and Jerry Zimmerman, MD, PhD

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      Linked Article

      • Corrigendum
        Annals of Emergency MedicineVol. 78Issue 3
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          Correction to “Early Care of Adults With Suspected Sepsis in the Emergency Department and Out-of-Hospital Environment: A Consensus-Based Task Force Report”
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      • Dynamic Fluid Response Measures to Guide Early Care of Adults With Suspected Sepsis in the Emergency Department and Out-of-Hospital Environment
        Annals of Emergency MedicineVol. 78Issue 4
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          We read with interest the article by Yealy et al1 titled “Early Care of Adults With Suspected Sepsis in the Emergency Department and Out-of-Hospital Environment: A Consensus-Based Task Force Report,” and we commend the authors on their generally comprehensive and timely report. While the consensus development process leverages methodological rigor, it is inherently susceptible to rapid obsolescence as the evidence base evolves. A potential consequence is a delay in the dissemination and implementation of high-quality evidence.
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      • In Reply to Ivor Douglas Letter to the Editor 2021-1053
        Annals of Emergency MedicineVol. 78Issue 4
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          We thank Douglas et al for their interest in our work. As noted in our manuscript, we used a multidisciplinary and multiorganizational approach to address the opportunities and limits of current guidelines on sepsis care.1 We specifically did not create a comprehensive and graded series of recommendations on early care, seeking instead to identify key concerns in current recommendations and care quality measures. We sought to address current controversies and help inform future guideline development and quality measures that bridge all acute care settings.
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