surviving_sepsis_campaign__international.21.pdf

ONLINE SPECIAL ARTICLE Downloaded from http://journals.lww.com/ccmjournal by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCy wCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdgGj2MwlZLeI= on 10/11/2023 Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 202...

ONLINE SPECIAL ARTICLE Downloaded from http://journals.lww.com/ccmjournal by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCy wCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdgGj2MwlZLeI= on 10/11/2023 Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021 KEY WORDS: adults; evidence-based medicine; guidelines; sepsis; septic shock Laura Evans1 Andrew Rhodes2 Waleed Alhazzani3 Massimo Antonelli4 INTRODUCTION Sepsis is life-threatening organ dysfunction caused by a dysregulated host response to infection (1). Sepsis and septic shock are major healthcare problems, impacting millions of people around the world each year and killing between one in three and one in six of those it affects (2–4). Early identification and appropriate management in the initial hours after the development of sepsis improve outcomes. The recommendations in this document are intended to provide guidance for the clinician caring for adult patients with sepsis or septic shock in the hospital setting. Recommendations from these guidelines cannot replace the clinician’s decision-making capability when presented with a unique patient’s clinical variables. These guidelines are intended to reflect best practice (Table 1). (References 5–24 are referred to in the Methodology section which can be accessed at Supplemental Digital Content: Methodology.) SCREENING AND EARLY TREATMENT Recommendation 1.  For hospitals and health systems, we recommend using a performance improvement program for sepsis, including sepsis screening for acutely ill, high-risk patients and standard operating procedures for treatment. Strong recommendation, moderate quality of evidence for screening. Strong recommendation, very low-quality evidence for standard operating procedures. Screening for Patients With Sepsis and Septic Shock Rationale Sepsis performance improvement programs generally consist of sepsis screening, education, measurement of sepsis bundle performance, patient outcomes, and actions for identified opportunities (25, 26). Despite some inconsistency, a meta-analysis of 50 observational studies on the effect of performance improvement programs showed that these programs were associated with better adherence to sepsis bundles along with a reduction in mortality (OR, 0.66; 95% CI, 0.61–0.72) in patients with sepsis and septic Critical Care Medicine Craig M. Coopersmith5 Craig French6 Flávia R. Machado7 Lauralyn Mcintyre8 Marlies Ostermann9 Hallie C. Prescott10 Christa Schorr11 Steven Simpson12 W. Joost Wiersinga13 Fayez Alshamsi14 Derek C. Angus15 Yaseen Arabi16 Luciano Azevedo17 Richard Beale18 Gregory Beilman19 Emilie Belley-Cote20 Lisa Burry21 Maurizio Cecconi22 John Centofanti23 Angel Coz Yataco24 Jan De Waele25 R. Phillip Dellinger26 This article is being simultaneously published in Critical Care Medicine (DOI: https://doi.org/10.1097/ CCM.0000000000005337) and Intensive Care Medicine (DOI: https://doi.org/10.1007/ s00134-021-06506-y). Copyright © 2021 by the Society of Critical Care Medicine and the European Society of Intensive Care Medicine. All Rights Reserved. www.ccmjournal.org     e1063 Evans et al Downloaded from http://journals.lww.com/ccmjournal by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCy wCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdgGj2MwlZLeI= on 10/11/2023 shock (27). The specific components of performance improvement did not appear to be as important as the presence of a program that included sepsis screening and metrics. Sepsis screening tools are designed to promote early identification of sepsis and consist of manual methods or automated use of the electronic health record (EHR). There is wide variation in diagnostic accuracy of these tools with most having poor predictive values, although the use of some was associated with improvements in care processes (28–31). A variety of clinical variables and tools are used for sepsis screening, such as systemic inflammatory response syndrome (SIRS) criteria, vital signs, signs of infection, quick Sequential Organ Failure Score (qSOFA) or Sequential Organ Failure Assessment (SOFA) criteria, National Early Warning Score (NEWS), or Modified Early Warning Score (MEWS) (26, 32). Machine learning may improve performance of screening tools, and in a meta-analysis of 42,623 patients from seven studies for predicting hospital acquired sepsis the pooled area under the receiving operating curve (SAUROC) (0.89; 95% CI, 0.86−0.92); sensitivity (81%; 95% CI, 80−81), and specificity (72%; 95% CI, 72−72) was higher for machine learning than the SAUROC for traditional screening tools such as SIRS (0.70), MEWS (0.50), and SOFA (0.78) (32). Screening tools may target patients in various locations, such as in-patient wards, emergency departments, or ICUs (28–30, 32). A pooled analysis of three RCTs did not demonstrate a mortality benefit of active screening (RR, 0.90; 95% CI, 0.51−1.58) (33–35). However, while there is wide variation in sensitivity and specificity of sepsis screening tools, they are an important component of identifying sepsis early for timely intervention. Standard operating procedures are a set of practices that specify a preferred response to specific clinical circumstances (36). Sepsis standard operating procedures, initially specified as Early Goal Directed Therapy have evolved to “usual care” which includes a standard approach with components of the sepsis bundle, early identification, lactate, cultures, antibiotics, and fluids (37). A large study examined the association between implementation of state-mandated sepsis protocols, compliance, and mortality. A retrospective cohort study of 1,012,410 sepsis admissions to 509 hospitals in the United States in a retrospective cohort examined mortality before (27 months) and after (30 months) implementation of New York state sepsis regulations, with a concurrent control population from four other states (38). In this comparative interrupted time series, mortality was lower in hospitals with higher compliance with achieving the sepsis bundles successfully. Lower resource countries may experience a different effect. A meta-analysis of two RCTs in Sub-Saharan Africa found higher mortality (RR, 1.26; 95% CI, 1.00−1.58) with standard operating procedures compared with usual care, while it was decreased in one observational study (adjusted hazard ratio [HR]; 95% CI, 0.55−0.98) (39). Kent Doi27 Bin Du28 Elisa Estenssoro29 Ricard Ferrer30 Charles Gomersall31 Carol Hodgson32 Morten Hylander Møller33 Theodore Iwashyna34 Shevin Jacob35 Ruth Kleinpell36 Michael Klompas37 Younsuck Koh38 Anand Kumar39 Arthur Kwizera40 Suzana Lobo41 Henry Masur42 Steven McGloughlin43 Sangeeta Mehta44 Yatin Mehta45 Mervyn Mer46 Mark Nunnally47 Simon Oczkowski48 Tiffany Osborn49 Elizabeth Papathanassoglou50 Anders Perner51 Michael Puskarich52 Jason Roberts53 William Schweickert54 Maureen Seckel55 Jonathan Sevransky56 Charles L. Sprung57 Tobias Welte58 Janice Zimmerman59 Mitchell Levy60 Recommendation 2.  We recommend against using qSOFA compared with SIRS, NEWS, or MEWS as a single screening tool for sepsis or septic shock. Strong recommendation, moderate-quality evidence. e1064     www.ccmjournal.org November 2021 • Volume 49 • Number 11 Online Special Article TABLE 1. Table of Current Recommendations and Changes From Previous 2016 Recommendations Recommendations 2021 Downloaded from http://journals.lww.com/ccmjournal by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCy wCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdgGj2MwlZLeI= on 10/11/2023 1. For hospitals and health systems, we recommend using a performance improvement program for sepsis, including sepsis screening for acutely ill, high-risk patients and standard operating procedures for treatment. Recommendation Strength and Quality of Evidence Changes From 2016 Recommendations Strong, moderate-quality evidence Changed from Best practice statement (for screening) Strong, very low-quality evidence (for standard operating procedures) “We recommend that hospitals and hospital systems have a performance improvement program for sepsis including sepsis screening for acutely ill, high-risk patients.” 2. We recommend against using qSOFA compared Strong, moderate-quality evidence NEW with SIRS, NEWS, or MEWS as a singlescreening tool for sepsis or septic shock. 3. For adults suspected of having sepsis, we suggest measuring blood lactate. Weak, low quality of evidence INITIAL RESUSCITATION 4. Sepsis and septic shock are medical emergencies, and we recommend that treatment and resuscitation begin immediately. Best practice statement 5. For patients with sepsis induced hypoperfusion Weak, low quality of evidence or septic shock we suggest that at least 30 mL/ kg of IV crystalloid fluid should be given within the first 3 hr of resuscitation. 6. For adults with sepsis or septic shock, we suggest using dynamic measures to guide fluid resuscitation, over physical examination, or static parameters alone. Weak, very low quality of evidence 7. For adults with sepsis or septic shock, we suggest guiding resuscitation to decrease serum lactate in patients with elevated lactate level, over not using serum lactate. Weak, low quality of evidence 8. For adults with septic shock, we suggest using capillary refill time to guide resuscitation as an adjunct to other measures of perfusion. Weak, low quality of evidence DOWNGRADE from Strong, low quality of evidence “We recommend that in the initial resuscitation from sepsis-induced hypoperfusion, at least 30 mL/kg of IV crystalloid fluid be given within the first 3 hr” NEW MEAN ARTERIAL PRESSURE 9. For adults with septic shock on vasopressors, we recommend an initial target mean arterial pressure (MAP) of 65 mm Hg over higher MAP targets. Strong, moderate-quality evidence ADMISSION TO INTENSIVE CARE 10. For adults with sepsis or septic shock who re- Weak, low quality of evidence quire ICU admission, we suggest admitting the patients to the ICU within 6 hr. Critical Care Medicine www.ccmjournal.org     e1065 Evans et al Recommendations 2021 Recommendation Strength and Quality of Evidence Changes From 2016 Recommendations INFECTION Downloaded from http://journals.lww.com/ccmjournal by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCy wCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdgGj2MwlZLeI= on 10/11/2023 11. For adults with suspected sepsis or septic Best practice statement shock but unconfirmed infection, we recommend continuously re-evaluating and searching for alternative diagnoses and discontinuing empiric antimicrobials if an alternative cause of illness is demonstrated or strongly suspected. 12. For adults with possible septic shock or a high likelihood for sepsis, we recommend administering antimicrobials immediately, ideally within 1 hr of recognition. Strong, low quality of evidence (Septic shock) Strong, very low quality of evidence (Sepsis without shock) CHANGED from previous: “We recommend that administration of intravenous antimicrobials should be initiated as soon as possible after recognition and within one hour for both a) septic shock and b) sepsis without shock” strong recommendation, moderate quality of evidence 13. For adults with possible sepsis without shock, we recommend rapid assessment of the likelihood of infectious versus noninfectious causes of acute illness. Best practice statement 14. For adults with possible sepsis without shock, Weak, very low quality of evidence we suggest a time-limited course of rapid investigation and if concern for infection persists, the administration of antimicrobials within 3 hr from the time when sepsis was first recognized. NEW from previous: “We recommend that administration of IV antimicrobials should be initiated as soon as possible after recognition and within 1 hr for both a) septic shock and b) sepsis without shock” strong recommendation, moderate quality of evidence 15. For adults with a low likelihood of infection and without shock, we suggest deferring antimicrobials while continuing to closely monitor the patient. Weak, very low quality of evidence NEW from previous: “We recommend that administration of IV antimicrobials should be initiated as soon as possible after recognition and within 1 hr for both a) septic shock and b) sepsis without shock“ strong recommendation, moderate quality of evidence 16. F  or adults with suspected sepsis or septic shock, Weak, very low quality of evidence we suggest against using procalcitonin plus clinical evaluation to decide when to start antimicrobials, as compared to clinical evaluation alone. 17. For adults with sepsis or septic shock at high risk of MRSA, we recommend using empiric antimicrobials with MRSA coverage over using antimicrobials without MRSA coverage. Best practice statement NEW from previous: “We recommend empiric broad-spectrum therapy with one or more antimicrobials for patients presenting with sepsis or septic shock to cover all likely pathogens (including bacterial and potentially fungal or viral coverage.” Strong recommendation, moderate quality of evidence e1066     www.ccmjournal.org November 2021 • Volume 49 • Number 11 Online Special Article Recommendations 2021 Downloaded from http://journals.lww.com/ccmjournal by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCy wCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdgGj2MwlZLeI= on 10/11/2023 18. For adults with sepsis or septic shock at low risk of MRSA, we suggest against using empiric antimicrobials with MRSA coverage, as compared with using antimicrobials without MRSA coverage. Recommendation Strength and Quality of Evidence Changes From 2016 Recommendations Weak, low quality of evidence NEW from previous: “We recommend empiric broad-spectrum therapy with one or more antimicrobials for patients presenting with sepsis or septic shock to cover all likely pathogens (including bacterial and potentially fungal or viral coverage.” Strong recommendation, moderate quality of evidence 19. F  or adults with sepsis or septic shock and high risk for multidrug resistant (MDR) organisms, we suggest using two antimicrobials with gram-negative coverage for empiric treatment over one gram-negative agent. Weak, very low quality of evidence 20. For adults with sepsis or septic shock and low risk for multidrug resistant (MDR) organisms, we suggest against using two gram-negative agents for empiric treatment, as compared to one gram-negative agent. Weak, very low quality of evidence 21. For adults with sepsis or septic shock, we Weak, very low quality of suggest against using double gram-negative evidence coverage once the causative pathogen and the susceptibilities are known. 22. For adults with sepsis or septic shock at high risk of fungal infection, we suggest using empiric antifungal therapy over no antifungal therapy. Weak, low quality of evidence NEW from previous: “We recommend empiric broad-spectrum therapy with one or more antimicrobials for patients presenting with sepsis or septic shock to cover all likely pathogens (including bacterial and potentially fungal or viral coverage.” Strong recommendation, moderate quality of evidence 23. For adults with sepsis or septic shock at low Weak, low quality of evidence risk of fungal infection, we suggest against empiric use of antifungal therapy NEW from previous: “We recommend empiric broad-spectrum therapy with one or more antimicrobials for patients presenting with sepsis or septic shock to cover all likely pathogens (including bacterial and potentially fungal or viral coverage. “ Strong recommendation, moderate quality of evidence 24. We make no recommendation on the use of antiviral agents. No recommendation 25. For adults with sepsis or septic shock, we suggest using prolonged infusion of beta-lactams for maintenance (after an initial bolus) over conventional bolus infusion. Weak, moderate-quality evidence Critical Care Medicine www.ccmjournal.org     e1067 Evans et al Recommendations 2021 Recommendation Strength and Quality of Evidence Downloaded from http://journals.lww.com/ccmjournal by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCy wCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdgGj2MwlZLeI= on 10/11/2023 26. For adults with sepsis or septic shock, we recommend optimising dosing strategies of antimicrobials based on accepted pharmacokinetic/pharmacodynamic (PK/PD) principles and specific drug properties. Best practice statement 27. F  or adults with sepsis or septic shock, we recommend rapidly identifying or excluding a specific anatomical diagnosis of infection that requires emergent source control and implementing any required source control intervention as soon as medically and logistically practical. Best practice statement 28. For adults with sepsis or septic shock, we recommend prompt removal of intravascular access devices that are a possible source of sepsis or septic shock after other vascular access has been established. Best practice statement 29. For adults with sepsis or septic shock, we suggest daily assessment for de-escalation of antimicrobials over using fixed durations of therapy without daily reassessment for de-escalation. Weak, very low quality of evidence 30. For adults with an initial diagnosis of sepsis or septic shock and adequate source control, we suggest using shorter over longer duration of antimicrobial therapy. Weak, very low quality of evidence 31. For adults with an initial diagnosis of sepsis or septic shock and adequate source control where optimal duration of therapy is unclear, we suggest using procalcitonin AND clinical evaluation to decide when to discontinue antimicrobials over clinical evaluation alone. Weak, low quality of evidence Changes From 2016 Recommendations HEMODYNAMIC MANAGEMENT 32. For adults with sepsis or septic shock, we recommend using crystalloids as first-line fluid for resuscitation. Strong, moderate-quality evidence 33. For adults with sepsis or septic shock, we suggest using balanced crystalloids instead of normal saline for resuscitation. Weak, low quality of evidence CHANGED from weak recommendation, low quality of evidence. “We suggest using either balanced crystalloids or saline for fluid resuscitation of patients with sepsis or septic shock” 34. For adults with sepsis or septic shock, we sug- Weak, moderate-quality evidence gest using albumin in patients who received large volumes of crystalloids. 35. For adults with sepsis or septic shock, we recommend against using starches for resuscitation. e1068     www.ccmjournal.org Strong, high-quality evidence November 2021 • Volume 49 • Number 11 Online Special Article Recommendations 2021 36. For adults with sepsis and septic shock, we suggest against using gelatin for resuscitation. Recommendation Strength and Quality of Evidence Changes From 2016 Recommendations Weak, moderate-quality evidence UPGRADE from weak recommendation, low quality of evidence Downloaded from http://journals.lww.com/ccmjournal by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCy wCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdgGj2MwlZLeI= on 10/11/2023 “We suggest using crystalloids over gelatins when resuscitating patients with sepsis or septic shock.” 37. For adults with septic shock, we recommend Strong using norepinephrine as the first-line agent over Dopamine. High-quality evidence other vasopressors. Vasopressin. Moderate-quality evidence Epinephrine. Low quality of evidence Selepressin. Low quality of evidence Angiotensin II. Very low-quality evidence 38. For adults with septic shock on norepinephrine with inadequate mean arterial pressure levels, we suggest adding vasopressin instead of escalating the dose of norepinephrine. Weak, moderate quality evidence 39. For adults with septic shock and inadequate mean arterial pressure levels despite norepinephrine and vasopressin, we suggest adding epinephrine. Weak, low quality of evidence 40. For adults with septic shock, we suggest against using terlipressin. Weak, low quality of evidence 41. For adults with septic shock and cardiac dysfunction with persistent hypoperfusion despite adequate volume status and arterial blood pressure, we suggest either adding dobutamine to norepinephrine or using epinephrine alone. Weak, low quality of evidence 42. For adults with septic shock and cardiac dysfunction with persistent hypoperfusion despite adequate volume status and arterial blood pressure, we suggest against using levosimendan. Weak, low quality of evidence 43. For adults with septic shock, we suggest invasive monitoring of arterial blood pressure over noninvasive monitoring, as soon as practical and if resources are available. Weak, very low quality of evidence 44. For adults with septic shock, we suggest starting vasopressors peripherally to restore mean arterial pressure rather than delaying initiation until a central venous access is secured. Weak, very low quality of evidence Critical Care Medicine NEW NEW www.ccmjournal.org     e1069 Evans et al Recommendations 2021 Downloaded from http://journals.lww.com/ccmjournal by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCy wCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdgGj2MwlZLeI= on 10/11/2023 45. There is insufficient evidence to make a recommendation on the use of restrictive versus liberal fluid strategies in the first 24 hr of resuscitation in patients with sepsis and septic shock who still have signs of hypoperfusion and volume depletion after the initial resuscitation. Recommendation Strength and Quality of Evidence Changes From 2016 Recommendations No recommendation NEW “We suggest using either balanced crystalloids or saline for fluid resuscitation of patients with sepsis or septic shock” Weak recommendation, low quality of evidence “We suggest using crystalloids over gelatins when resuscitating patients with sepsis or septic shock.” Weak recommendation, low quality of evidence VENTILATION 46.There is insufficient evidence to make a recommendation on the use of conservative oxygen targets in adults with sepsis-induced hypoxemic respiratory failure. No recommendation 47. For adults with sepsis-induced hypoxemic respiratory failure, we suggest the use of high flow nasal oxygen over noninvasive ventilation. Weak, low quality of evidence NEW 48. There is insufficient evidence to make a recom- No recommendation mendation on the use of noninvasive ventilation in comparison to invasive ventilation for adults with sepsis-induced hypoxemic respiratory failure. 49. For adults with sepsis-induced ARDS, we recommend using a low tidal volume ventilation strategy (6 mL/kg), over a high tidal volume strategy (> 10 mL/kg). Strong, high-quality evidence 50. For adults with sepsis-induced severe ARDS, we recommend using an upper limit goal for plateau pressures of 30 cm H2O, over higher plateau pressures. Strong, moderate-quality evidence 51. For adults with moderate to severe sepsisinduced ARDS, we suggest using higher PEEP over lower PEEP. Weak, moderate-quality evidence 52. For adults with sepsis-induced respiratory failure (without ARDS), we suggest using low tidal volume as compared with high tidal volume ventilation. Weak, low quality of evidence 53. F  or adults with sepsis-induced moderatesevere ARDS, we suggest using traditional recruitment maneuvers. Weak, moderate-quality evidence 54. When using recruitment maneuvers, we recommend against using incremental PEEP titration/strategy. Strong, moderate-quality evidence 55. For adults with sepsis-induced moderatesevere ARDS, we recommend using prone ventilation for greater than 12 hr daily. Strong, moderate-quality evidence e1070     www.ccmjournal.org November 2021 • Volume 49 • Number 11 Online Special Article Recommendations 2021 Downloaded from http://journals.lww.com/ccmjournal by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCy wCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdgGj2MwlZLeI= on 10/11/2023 56. For adults with sepsis induced moderatesevere ARDS, we suggest using intermittent NMBA boluses, over NMBA continuous infusion. Recommendation Strength and Quality of Evidence Changes From 2016 Recommendations Weak, moderate-quality evidence 57. For adults with sepsis-induced severe ARDS, Weak, low quality of evidence we suggest using Veno-venous (VV) ECMO when conventional mechanical ventilation fails in experienced centers with the infrastructure in place to support its use. NEW ADDITIONAL THERAPIES 58. For adults with septic shock and an ongoing requirement for vasopressor therapy we suggest using IV corticosteroids. Weak, moderate-quality evidence UPGRADE from Weak recommendation, low quality of evidence “We suggest against using IV hydrocortisone to treat septic shock patients if adequate fluid resuscitation and vasopressor therapy are able to restore hemodynamic stability (see goals for Initial Resuscitation). If this is not achievable, we suggest IV hydrocortisone at a dose of 200 mg/day.” 59. For adults with sepsis or septic shock we sug- Weak, low quality of evidence gest against using polymyxin B hemoperfusion. NEW from previous: “We make no recommendation regarding the use of blood purification techniques” 60. There is insufficient evidence to make a recom- No recommendation mendation on the use of other blood purification techniques. 61. For adults with sepsis or septic shock we recommend using a restrictive (over liberal) transfusion strategy. Strong, moderate-quality evidence 62. For adults with sepsis or septic shock we suggest against using IV immunoglobulins. Weak, low quality of evidence 63. For adults with sepsis or septic shock, and who have risk factors for gastrointestinal (GI) bleeding, we suggest using stress ulcer prophylaxis. Weak, moderate-quality evidence 64. For adults with sepsis or septic shock, we recommend using pharmacologic venous thromboembolism (VTE) prophylaxis unless a contraindication to such therapy exists. Strong, moderate-quality evidence 65. For adults with sepsis or septic shock, we recommend using low molecular weight heparin over unfractionated heparin for VTE prophylaxis Strong, moderate-quality evidence 66. For adults with sepsis or septic shock, we Weak, low quality of evidence suggest against using mechanical VTE prophylaxis, in addition to pharmacological prophylaxis, over pharmacologic prophylaxis alone. Critical Care Medicine www.ccmjournal.org     e1071 Evans et al Recommendations 2021 Recommendation Strength and Quality of Evidence Downloaded from http://journals.lww.com/ccmjournal by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCy wCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdgGj2MwlZLeI= on 10/11/2023 67. In adults with sepsis or septic shock and AKI, we suggest using either continuous or intermittent renal replacement therapy. Weak, low quality of evidence 68. In adults with sepsis or septic shock and AKI, with no definitive indications for renal replacement therapy, we suggest against using renal replacement therapy. Weak, moderate-quality evidence 69. For adults with sepsis or septic shock, we recommend initiating insulin therapy at a glucose level of ≥ 180mg/dL (10 mmol/L). Strong, moderate-quality evidence 70. For adults with sepsis or septic shock we suggest against using IV vitamin C. Weak, low quality of evidence 71. For adults with septic shock and hypoperfusion-induced lactic acidemia, we suggest against using sodium bicarbonate therapy to improve hemodynamics or to reduce vasopressor requirements. Weak, low quality of evidence 72. F  or adults with septic shock and severe metabolic acidemia (pH ≤ 7.2) and acute kidney injury (AKIN score 2 or 3), we suggest using sodium bicarbonate therapy Weak, low quality of evidence 73. For adult patients with sepsis or septic shock who can be fed enterally, we suggest early (within 72 hr) initiation of enteral nutrition. Weak, very low quality of evidence Changes From 2016 Recommendations NEW LONG-TERM OUTCOMES AND GOALS OF CARE 74. For adults with sepsis or septic shock, we recommend discussing goals of care and prognosis with patients and families over no such discussion. Best practice statement 75. For adults with sepsis or septic shock, we suggest addressing goals of care early (within 72 hr) over late (72 hr or later). Weak, low quality of evidence 76. For adults with sepsis or septic shock, there is insufficient evidence to make a recommendation on any specific standardized criterion to trigger goals of care discussion. No recommendation 77. For adults with sepsis or septic shock, we recommend that the principles of palliative care (which may include palliative care consultation based on clinician judgement) be integrated into the treatment plan, when appropriate, to address patient and family symptoms and suffering. Best practice statement 78. For adults with sepsis or septic shock, we suggest against routine formal palliative care consultation for all patients over palliative care consultation based on clinician judgement. Weak, low quality of evidence e1072     www.ccmjournal.org November 2021 • Volume 49 • Number 11 Online Special Article Recommendations 2021 Recommendation Strength and Quality of Evidence Downloaded from http://journals.lww.com/ccmjournal by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCy wCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdgGj2MwlZLeI= on 10/11/2023 79. For adult survivors of sepsis or septic shock and their families, we suggest referral to peer support groups over no such referral. Weak, very low quality of evidence 80. For adults with sepsis or septic shock, we suggest using a handoff process of critically important information at transitions of care over no such handoff process. Weak, very low quality of evidence 81. For adults with sepsis or septic shock, there is insufficient evidence to make a recommendation on the use of any specific structured handoff tool over usual handoff processes. No recommendation 82. For adults with sepsis or septic shock and their families, we recommend screening for economic and social support (including housing, nutritional, financial, and spiritual support), and make referrals where available to meet these needs. Best practice statement 83. For adults with sepsis or septic shock and their families, we suggest offering written and verbal sepsis education (diagnosis, treatment, and post-ICU/post-sepsis syndrome) prior to hospital discharge and in the follow-up setting. Weak, very low quality of evidence 84. For adults with sepsis or septic shock and their families, we recommend the clinical team provide the opportunity to participate in shared decision making in post-ICU and hospital discharge planning to ensure discharge plans are acceptable and feasible. Best practice statement 85. For adults with sepsis and septic shock and their families, we suggest using a critical care transition program, compared with usual care, upon transfer to the floor. Weak, very low quality of evidence 86. For adults with sepsis and septic shock, we recommend reconciling medications at both ICU and hospital discharge. Best practice statement 87. For adult survivors of sepsis and septic shock and their families, we recommend including information about the ICU stay, sepsis and related diagnoses, treatments, and common impairments after sepsis in the written and verbal hospital discharge summary. Best practice statement 88. For adults with sepsis or septic shock who developed new impairments, we recommend hospital discharge plans include follow-up with clinicians able to support and manage new and long-term sequelae. Best practice statement Critical Care Medicine Changes From 2016 Recommendations www.ccmjournal.org     e1073 Evans et al Recommendations 2021 Recommendation Strength and Quality of Evidence Downloaded from http://journals.lww.com/ccmjournal by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCy wCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdgGj2MwlZLeI= on 10/11/2023 89. F  or adults with sepsis or septic shock and their families, there is insufficient evidence to make a recommendation on early posthospital discharge follow-up compared with routine post-hospital discharge follow-up. No recommendation 90. For adults with sepsis or septic shock, there is insufficient evidence to make a recommendation for or against early cognitive therapy. No recommendation 91. For adult survivors of sepsis or septic shock, we recommend assessment and follow-up for physical, cognitive, and emotional problems after hospital discharge. Best practice statement 92. For adult survivors of sepsis or septic shock, we suggest referral to a post-critical illness follow-up program if available. Weak, very low quality of evidence 93. F  or adult survivors of sepsis or septic shock receiving mechanical ventilation for > 48hr or an ICU stay of > 72 hr, we suggest referral to a post-hospital rehabilitation program. Weak, very low quality of evidence Rationale The qSOFA uses three variables to predict death and prolonged ICU stay in patients with known or suspected sepsis: a Glasgow Coma Score < 15, a respiratory rate ≥ 22 breaths/min and a systolic blood pressure ≤ 100 mm Hg. When any two of these variables are present simultaneously, the patient is considered qSOFA positive. Data analysis used to support the recommendations of the Third International Consensus Conference on the Definitions of Sepsis identified qSOFA as a predictor of poor outcome in patients with known or suspected infection, but no analysis was performed to support its use as a screening tool (5). Since that time numerous studies have investigated the potential use of the qSOFA as a screening tool for sepsis (40–42). The results have been contradictory as to its usefulness. Studies have shown that qSOFA is more specific but less sensitive than having two of four SIRS criteria for early identification of infection induced organ dysfunction (40–43). Neither SIRS nor qSOFA are ideal screening tools for sepsis and the bedside clinician needs to understand the limitations of each. In the original derivation study, authors found that only e1074     www.ccmjournal.org Changes From 2016 Recommendations 24% of infected patients had a qSOFA score 2 or 3, but these patients accounted for 70% of poor outcomes (5). Similar findings have also been found when comparing against the National Early warning Score (NEWS) and the Modified Early warning Score (MEWS) (44). Although the presence of a positive qSOFA should alert the clinician to the possibility of sepsis in all resource settings; given the poor sensitivity of the qSOFA, the panel issued a strong recommendation against its use as a single screening tool. Recommendation 3. For adults suspected of having sepsis, we suggest measuring blood lactate. Weak recommendation, low-quality evidence. Rationale The association of lactate level with mortality in patients with suspected infection and sepsis is well established (45, 46). Its use is currently recommended as part of the SSC Hour-1 sepsis bundle for those patients with sepsis (47, 48), and an elevated November 2021 • Volume 49 • Number 11 Online Special Article Downloaded from http://journals.lww.com/ccmjournal by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCy wCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdgGj2MwlZLeI= on 10/11/2023 lactate is part of the Sepsis-3 definition of septic shock (49). It has been suggested that lactate can also be used to screen for the presence of sepsis among undifferentiated adult patients with clinically suspected (but not confirmed) sepsis. Several studies have assessed the use of lactate in this context (50–52). The lactate cutoffs determining an elevated level ranged from 1.6−2.5 mmol/L, although diagnostic characteristics were similar regardless of the cutoff. Sensitivities range from 66−83%, with specificities ranging from 80−85%. Pooled positive and negative likelihood ratios from the three studies are 4.75 and 0.29, respectively. Studies showed an association between the use of point-of-care lactate measurements at presentation and reduced mortality; however, the results are inconsistent (53). In summary, the presence of an elevated or normal lactate level significantly increases or decreases, respectively, the likelihood of a final diagnosis of sepsis in patients with suspected sepsis. However, lactate alone is neither sensitive nor specific enough to rule-in or ruleout the diagnosis on its own. Lactate testing may not be readily available in many resource-limited settings (54–61). Therefore, we issued a weak recommendation favoring the use of serum lactate as an adjunctive test to modify the pretest probability of sepsis in patients with suspected but not confirmed sepsis. Initial Resuscitation Recommendations 4. Sepsis and septic shock are medical emergencies, and we recommend that treatment and resuscitation begin immediately. Best practice statement. 5. For patients with sepsis induced hypoperfusion or septic shock we suggest that at least 30 mL/kg of IV crystalloid fluid should be given within the first 3 hours of resuscitation. Weak recommendation, low-quality evidence. 6. For adults with sepsis or septic shock, we suggest using dynamic measures to guide fluid resuscitation over physical examination or static parameters alone. Weak recommendation, very low-quality evidence. Remarks: Dynamic parameters include response to a passive leg raise or a fluid bolus, using stroke volume (SV), stroke volume variation (SVV), pulse pressure variation (PPV), or echocardiography, where available. Critical Care Medicine 7. For adults with sepsis or septic shock, we suggest guiding resuscitation to decrease serum lactate in patients with elevated lactate level, over not using serum lactate. Weak recommendation, low-quality evidence. Remarks: During acute resuscitation, serum lactate level should be interpreted considering the clinical context and other causes of elevated lactate. 8. For adults with septic shock, we suggest using capillary refill time to guide resuscitation as an adjunct to other measures of perfusion. Weak recommendation, low-quality evidence. Rationale Timely, effective fluid resuscitation is crucial for the stabilization of sepsis-induced tissue hypoperfusion in sepsis and septic shock. Previous guidelines recommend initiating appropriate resuscitation immediately upon recognition of sepsis or septic shock and having a low threshold for commencing it in those patients where sepsis is not proven but is suspected. Although the evidence stems from observational studies, this recommendation is considered a best practice and there are no new data suggesting that a change is needed. The 2016 SSC guideline issued a recommendation for using a minimum of 30 mL/kg (ideal body weight) of IV crystalloids in initial fluid resuscitation. This fixed volume of initial resuscitation was based on observational evidence (62). There are no prospective intervention studies comparing different volumes for initial resuscitation in sepsis or septic shock. A retrospective analysis of adults presenting to an emergency department with sepsis or septic shock showed that failure to receive 30 mL/kg of crystalloid fluid therapy within 3 hours of sepsis onset was associated with increased odds of in-hospital mortality, delayed resolution of hypotension and increased length of stay in ICU, irrespective of comorbidities, including end-stage kidney disease and heart failure (63). In the PROCESS (64), ARISE (65) and PROMISE (66) trials, the average volume of fluid received pre-randomization was also in the range of 30 mL/kg, suggesting that this fluid volume has been adopted in routine clinical practice (67). Most patients require continued fluid administration following initial resuscitation. Such administration needs to be balanced with the risk of fluid www.ccmjournal.org     e1075 Evans et al Downloaded from http://journals.lww.com/ccmjournal by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCy wCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdgGj2MwlZLeI= on 10/11/2023 accumulation and potential harm associated with fluid overload, especially prolonged ventilation, progression of acute kidney injury (AKI) and increased mortality. One of the most important principles of managing complex septic patients is the need for a detailed initial assessment and ongoing re-evaluation of the response to treatment. To avoid over- and under-resuscitation, fluid administration beyond the initial resuscitation should be guided by careful assessment of intravascular volume status and organ perfusion. Heart rate, central venous pressure (CVP) and systolic blood pressure alone are poor indicators of fluid status. Dynamic measures have demonstrated better diagnostic accuracy at predicting fluid responsiveness compared with static techniques. Dynamic measures include passive leg raising combined with cardiac output (CO) measurement, fluid challenges against stroke volume (SV), systolic pressure or pulse pressure, and increases of SV in response to changes in intrathoracic pressure. In a systematic review and meta-analysis, dynamic assessment to guide fluid therapy was associated with reduced mortality (RR, 0.59; 95% CI, 0.42 to 0.83), ICU length of stay (MD -1.16 days; 95% CI, -1.97 to -0.36), and duration of mechanical ventilation (-2.98 hours; 95% CI, -5.08 to -0.89) (3). However, in one other meta-analysis, there was no significant difference in mortality between septic patients resuscitated with a volume responsiveness-guided approach compared with standard resuscitative strategies (68). Most data arise from high income settings and a paucity of evidence exists in resource-limited settings to guide optimal titration of fluid resuscitation as well as the appropriate safety endpoints. An RCT in patients with sepsis and hypotension in Zambia showed that early protocolized resuscitation with administration of IV fluids guided by jugular venous pressure, respiratory rate, and arterial oxygen saturation only, was associated with significantly more fluid administration in the first 6 hours (median 3.5 L [IQR, 2.7−4.0] versus 2.0 L [IQR, 1.0–2.5]) and higher hospital mortality (48.1% versus 33%) than standard care (69). If fluid therapy beyond the initial 30 mL/kg administration is required, clinicians may use repeated small boluses guided by objective measures of SV and/or CO. In post-cardiac surgery patients, fluid challenges of 4 mL/kg compared to 1 to 3 mL/kg increased the sensitivity of detecting fluid responders and nonresponders based on measurement of CO (70). In resource-limited e1076     www.ccmjournal.org regions where measurement of CO or SV may not be possible, a >15% increase in pulse pressure could indicate that the patient is fluid responsive utilizing a passive leg-raise test for 60−90 seconds (71, 72). Serum lactate is an important biomarker of tissue hypoxia and dysfunction, but is not a direct measure of tissue perfusion (73). Recent definitions of septic shock include increases in lactate as evidence of cellular stress to accompany refractory hypotension (1). Previous iterations of these guidelines have suggested using lactate levels as a target of resuscitation in the early phases of sepsis and septic shock, based on earlier studies related to goal-directed therapy and meta-analyses of multiple studies targeting reductions in serum lactate in comparison with “standard care” or increases in central venous oxygen saturation (74, 75). The panel recognizes that normal serum lactate levels are not achievable in all patients with septic shock, but these studies support resuscitative strategies that decrease lactate toward normal. Serum lactate level should be interpreted considering the clinical context and other causes of elevated lactate. As with sepsis screening, lactate measurement may not always be available in some resource-limited settings. When advanced hemodynamic monitoring is not available, alternative measures of organ perfusion may be used to evaluate the effectiveness and safety of volume administration. Temperature of the extremities, skin mottling and capillary refill time (CRT) have been validated and shown to be reproducible signs of tissue perfusion (76, 77). The ANDROMEDA-SHOCK study evaluated whether a resuscitation strategy targeting CRT normalization was more effective than a resuscitation strategy aiming at normalization or decreasing lactate levels by 20% every 2 hours in the first 8 hours of septic shock (58). At day 3, the CRT group had significantly less organ dysfunction as assessed by SOFA score (mean SOFA score 5.6 [SD 4.3] versus 6.6 [SD 4.7]; p = 0.045). Twenty-eight−day mortality was 34.9% in the peripheral perfusion group and 43.4% in the lactate group, but this difference did not reach statistical significance (HR, 0.75; 95% CI, 0.55–1.02). Despite the absence of a clear effect on mortality, using CRT during resuscitation has physiologic plausibility and is easily performed, noninvasive, and no cost. However, this approach should be augmented by careful, frequent, and comprehensive patient evaluation to predict or recognize fluid overload early, particularly November 2021 • Volume 49 • Number 11 Online Special Article where critical care resources are constrained. Relevant consideration of the background pathology or pathological processes pertinent to the patient should also inform management (69, 78). Downloaded from http://journals.lww.com/ccmjournal by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCy wCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdgGj2MwlZLeI= on 10/11/2023 Mean Arterial Pressure Recommendation 9. For adults with septic shock on vasopressors, we recommend an initial target mean arterial pressure (MAP) of 65 mm Hg over higher MAP targets. Strong recommendation, moderate-quality evidence. care group. Among 2,463 analyzed patients, there was significantly less exposure to vasopressors in the intervention group, measured by duration of vasopressor infusion and total vasopressor doses expressed in norepinephrine equivalents. Ninety-day mortality in the permissive hypotension and usual care groups was similar (41.0% vs 43.8%). Given the lack of advantage associated with higher MAP targets and the lack of harm among elderly patients with MAP targets of 60–65 mm Hg, the panel recommends targeting a MAP of 65 mm Hg in the initial resuscitation of patients with septic shock who require vasopressors. Rationale MAP is a key determinant of mean systemic filling pressure, which in turn is the major driver of venous return and CO. Increasing MAP therefore usually results in increased tissue blood flow and augments the supply side of tissue perfusion. While some tissues, such as the brain and kidneys have the ability to autoregulate blood flow, MAPs below a threshold, usually understood to be approximately 60 mm Hg, are associated with decreased organ perfusion, which tracks linearly with MAP (79). Previous SSC guidelines recommended targeting a MAP of greater than 65 mm Hg for initial resuscitation. The recommendation was based principally on a RCT in septic shock comparing patients who were given vasopressors to target a MAP of 65−70 mm Hg, versus a target of 80−85 mm Hg (80). This study found no difference in mortality, although a subgroup analysis demonstrated a 10.5% absolute reduction in renal replacement therapy (RRT) with higher MAP targets among patients with chronic hypertension. Additionally, targeting higher MAP with vasopressors was associated with a higher risk of atrial fibrillation. A limitation of this study was that the average MAP in both arms exceeded the targeted range. A meta-analysis of two RCTs on this topic supported that higher MAP targets did not improve survival in septic shock (RR, 1.05; 95% CI, 0.90−1.23) (81). A recent RCT, monitored to ensure protocol and MAP target compliance, compared a “permissive hypotension” (MAP 60–65 mm Hg) group with a “usual care” group that received vasopressors and MAP targets set by the treating physician in patients aged 65 years and older with septic shock (82, 83). The intervention group in this study achieved a mean MAP of 66.7 mm Hg, compared with 72.6 mm Hg in the usual Critical Care Medicine Admission to Intensive Care Recommendation 10. For adults with sepsis or septic shock who require ICU admission, we suggest admitting the patients to the ICU within 6 hours. Weak recommendation, low-quality evidence. Rationale The outcome of critically ill patients depends on timely application of critical care interventions in an appropriate environment. Outside the ICU, septic patients are typically seen in the emergency department (ED) and hospital wards. Delayed admissions of critically ill patients from ED are associated with decreased sepsis bundle compliance and increased mortality, ventilator duration, and ICU and hospital length of stay (84). Data on the optimal time for transfer to the ICU stem from observational studies and registry databases. In an observational study of 401 ICU patients, authors reported an increase in ICU mortality of 1.5% for each hour delay of ED to ICU transfer (85). A retrospective observational study of 14,788 critically ill patients in the Netherlands showed a higher hospital mortality for the higher ED to ICU time quintiles (2.4– 3.7 hr and > 3.7 hr) compared with the lowest ED to ICU time quintile (< 1.2hr) (86). When adjusted for severity of illness, an ED to ICU time > 2.4 hr was associated with increased hospital mortality in patients with higher illness severity (ORs of 1.20 [95% CI, 1.03– 1.39]). Patients with sepsis were not studied separately. Another study evaluated 50,322 ED patients admitted to 120 US ICUs (87). Mortality increased when ED stay exceeded 6 hours (17% vs 12.9%, p < 0.001). www.ccmjournal.org     e1077 Evans et al Downloaded from http://journals.lww.com/ccmjournal by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCy wCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdgGj2MwlZLeI= on 10/11/2023 Among hospital survivors, the delayed admission group had a longer hospital stay, higher mortality, and higher rates of mechanical ventilation and central venous catherization. Similarly, another study of 12,380 ward patients in 48 hospitals in the United Kingdom showed that (88) delayed admission to ICU led to higher 90-day mortality and further physiological deterioration. Based on existing data, timely admission of critically ill patients to an ICU environment may result in better patient outcomes. There is also evidence of improved patient satisfaction, increased patient safety, better patient flow and improved staff morale (89). However, although critical care services are likely best delivered in an ICU environment, there are multiple reasons why immediate transfer of critically ill patients with sepsis to an ICU may not always be possible, in particular in lower- and middle-income countries (LMIC), where ICU bed availably can be limited. In this case, regular assessment, evaluation, and appropriate treatment should not be delayed, independent of patient location. INFECTION Diagnosis of Infection Recommendation 11. For adults with suspected sepsis or septic shock but unconfirmed infection, we recommend continuously re-evaluating and searching for alternative diagnoses and discontinuing empiric antimicrobials if an alternative cause of illness is demonstrated or strongly suspected. Best practice statement. Rationale In previous versions of these guidelines, we highlighted the importance of obtaining a full screen for infectious agents prior to starting antimicrobials wherever it is possible to do so in a timely fashion (12, 13). As a best practice statement, we recommended that appropriate routine microbiologic cultures (including blood) should be obtained before starting antimicrobial therapy in patients with suspected sepsis and septic shock if it results in no substantial delay in the start of antimicrobials (i.e., < 45 min). This recommendation has not been updated in this version but remains as valid as before. The signs and symptoms of sepsis are nonspecific and often mimic multiple other diseases (90–92). e1078     www.ccmjournal.org Because there is no “gold standard” test to diagnose sepsis, the bedside provider cannot have a differential diagnosis of sepsis alone in a patient with organ dysfunction. Indeed, a third or more of patients initially diagnosed with sepsis turn out to have noninfectious conditions (90, 93, 94). Best practice is to continually assess the patient to determine if other diagnoses are more or less likely, especially because a patient’s clinical trajectory can evolve significantly after hospital admission, increasing or decreasing the likelihood of a diagnosis of sepsis. With this uncertainty, there can be significant challenges in determining when it is “appropriate” to de-escalate or discontinue antibiotics. Another major challenge is implementing a system that reminds clinicians to focus on the fact that the patient is still receiving antibiotics each day, especially as providers rotate in and out of the care team. Systems that promote such reassessment by automatic stop orders, electronic prompts, or mandatory check lists all seem useful in theory, but each has disadvantages in terms of provider acceptance or assuring that providers thoughtfully assess the need for antibiotics rather than checking a box in the electronic record or reflexively acknowledging a prompt, without considering its underlying rationale (95). We did not identify any direct or indirect evidence assessing this important issue. Thus, clinicians are strongly encouraged to discontinue antimicrobials if a non-infectious syndrome (or an infectious syndrome that does not benefit from antimicrobials) is demonstrated or strongly suspected. Since this situation is not always apparent, continued reassessment of the patient should optimize the chances of infected patients receiving antimicrobial therapy and non-infected patients avoiding therapy that is not indicated. Time to Antibiotics Recommendations 12. For adults with possible septic shock or a high likelihood for sepsis, we recommend administering antimicrobials immediately, ideally within one hour of recognition. Strong recommendation, low quality of evidence (septic shock) Strong recommendation, very low quality of evidence (sepsis without shock) November 2021 • Volume 49 • Number 11 Online Special Article Downloaded from http://journals.lww.com/ccmjournal by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCy wCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdgGj2MwlZLeI= on 10/11/2023 13. For adults with possible sepsis without shock, we recommend rapid assessment of the likelihood of infectious versus non-infectious causes of acute illness. Best practice statement. Remarks: Rapid assessment includes history and clinical examination, tests for both infectious and non-infectious causes of acute illness and immediate treatment for acute conditions that can mimic sepsis. Whenever possible this should be completed within 3 hours of presentation so that a decision can be made as to the likelihood of an infectious cause of the patient’s presentation and timely antimicrobial therapy provided if the likelihood of sepsis is thought to be high. 14. For adults with possible sepsis without shock, we suggest a time-limited course of rapid investigation and if concern for infection persists, the administration of antimicrobials within 3 hours from the time when sepsis was first recognized. Weak recommendation, very low quality of evidence. 15.  or adults with a low likelihood of infection F and without shock, we suggest deferring antimicrobials while continuing to closely monitor the patient. Weak recommendation, very low quality of evidence. Rationale Early administration of appropriate antimicrobials is one of the most effective interventions to reduce mortality in patients with sepsis (96–98). Delivering antimicrobials to patients with sepsis or septic shock should therefore be treated as an emergency. The imperative to provide antimicrobials as early as possible, however, must be balanced against the potential harms associated with administering unnecessary antimicrobials to patients without infection (99, 100). These include a range of adverse events such as allergic or hypersensitivity reactions, kidney injury, thrombocytopenia, Clostridioides difficile infection, and antimicrobial resistance (101–106). Accurately diagnosing sepsis is challenging as sepsis can present in subtle ways, and some presentations that first appear to be sepsis turn out to be noninfectious conditions (90, 93, 107, 108). Evaluating the likelihood of infection and severity of illness for each patient with suspected sepsis should inform the necessity and urgency of antimicrobials (99, 100). The mortality reduction associated with early antimicrobials appears strongest in patients with septic shock, where studies have reported a strong association between time to antibiotics and death in patients with septic shock but weaker associations in patients Critical Care Medicine without septic shock (98, 109, 110). In a study of 49,331 patients treated at 149 New York hospitals, each additional hour of time from ED arrival to administration of antimicrobials was associated with 1.04 increased odds of in-hospital mortality, p < 0.001 (1.07 (95% CI, 1.05−1.09) for patients receiving vasopressors vs. 1.01 (95% CI, 0.99−1.04) for patients not on vasopressors) (98). In a study of 35,000 patients treated at Kaiser Permanente Northern California, each additional hour of time from ER arrival to administration of antimicrobials was associated with 1.09 increased odds of in-hospital mortality (1.07 for patients with “severe” sepsis [lactate ≥ 2, at least one episode of hypotension, required noninvasive or invasive mechanical ventilation or has organ dysfunction] and 1.14 for patients with septic shock); which equated to a 0.4% absolute mortality increase for “severe” sepsis and a 1.8% absolute increase for septic shock (110). Finally, in a study of 10,811 patients treated in four Utah hospitals, each hour delay in time from ED arrival to administration of antimicrobials was associated with 1.16 increased odds of in-hospital and 1.10 increased odds of 1-year mortality (1.13 in patients with hypotension vs 1.09 in patients without hypotension) (111). Other studies, however, did not observe an association between antimicrobial timing and mortality (112–117). It should be noted that all the aforementioned studies were observational analyses and hence at risk of bias due to insufficient sample size, inadequate risk adjustment, blending together the effects of large delays until antibiotics with short delays, or other study design issues (118). In patients with sepsis without shock, the association between time to antimicrobials and mortality within the first few hours from presentation is less consistent (98, 110). Two RCTs have been published (119, 120); one failed to achieve a difference in time-to-antimicrobials between arms (120) and the other found no significant difference in mortality despite a 90-minute difference in median time interval to antimicrobial administration (119). Obs