Elisa Estenssoro

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). TABLE 1. - Table of Current Recommendations and Changes From Previous 2016 Recommendations Recommendations 2021 Recommendation Strength and Quality of Evidence Changes From 2016 Recommendations 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 , moderate-quality evidence (for screening) Changed from Best practice statement "We recommend that hospitals and hospital systems have a performance improvement program for sepsis including sepsis screening for acutely ill, high-risk patients." Strong , very low-quality evidence (for standard operating procedures) 2. We recommend against using qSOFA compared with SIRS, NEWS, or MEWS as a single-screening tool for sepsis or septic shock. Strong , moderate-quality evidence NEW 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 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. 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" 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 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 require ICU admission, we suggest admitting the patients to the ICU within 6 hr. Weak , low quality of evidence INFECTION 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 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) 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 , very low quality of evidence (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, 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. 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 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. For adults with suspected sepsis or septic shock, we suggest against using procalcitonin plus clinical evaluation to decide when to start antimicrobials, as compared to clinical evaluation alone. Weak , very low quality of evidence 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 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. 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. For 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 suggest against using double gram-negative coverage once the causative pathogen and the susceptibilities are known. Weak , very low quality of evidence 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 risk of fungal infection, we suggest against empiric use of 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 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 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. For 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 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 suggest using albumin in patients who received large volumes of crystalloids. Weak , moderate-quality evidence 35. For adults with sepsis or septic shock, we recommend against using starches for resuscitation. Strong , high-quality evidence 36. For adults with sepsis and septic shock, we suggest against using gelatin for resuscitation. Weak , moderate-quality evidence UPGRADE from weak recommendation , low quality of evidence "We suggest using crystalloids over gelatins when resuscitating patients with sepsis or septic shock." 37. For adults with septic shock, we recommend using norepinephrine as the first-line agent over other vasopressors. Strong Dopamine. High-quality evidence 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 NEW 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 NEW 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. 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 recommendation on the use of noninvasive ventilation in comparison to invasive ventilation for adults with sepsis-induced hypoxemic respiratory failure. No recommendation 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 sepsis-induced 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. For adults with sepsis-induced moderate-severe 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 moderate-severe ARDS, we recommend using prone ventilation for greater than 12 hr daily. Strong , moderate-quality evidence 56. For adults with sepsis induced moderate-severe ARDS, we suggest using intermittent NMBA boluses, over NMBA continuous infusion. Weak , moderate-quality evidence 57. For adults with sepsis-induced severe ARDS, we suggest using Veno-venous (VV) ECMO when conventional mechanical ventilation fails in experienced centers with the infrastructure in place to support its use. Weak , low quality of evidence 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 suggest against using polymyxin B hemoperfusion. Weak , low quality of evidence NEW from previous: "We make no recommendation regarding the use of blood purification techniques" 60. There is insufficient evidence to make a recommendation on the use of other blood purification techniques. No recommendation 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 suggest against using mechanical VTE prophylaxis, in addition to pharmacological prophylaxis, over pharmacologic prophylaxis alone. Weak , low quality of evidence 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 NEW 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. For 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 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 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 89. For adults with sepsis or septic shock and their families, there is insufficient evidence to make a recommendation on early post-hospital 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. For 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 (References 5–24 are referred to in the Methodology section which can be accessed at Supplemental Digital Content: Methodology.) SCREENING AND EARLY TREATMENT Screening for Patients With Sepsis and Septic Shock - 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. 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 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 Sepsis standard operating as Early have to which a standard with components of the sepsis early and A large the between of sepsis and A of sepsis to hospitals in the in a mortality and after of sepsis with a control from other In this time mortality was lower in hospitals with higher with the sepsis bundles may a A meta-analysis of two RCTs in higher mortality (RR, 95% CI, with standard operating procedures compared with usual care, while it was in one observational 95% CI, - Recommendation 2. We recommend against using qSOFA compared with SIRS, NEWS, or MEWS as a screening tool for sepsis or septic shock. Strong recommendation, moderate-quality evidence. Rationale The qSOFA three variables to and prolonged ICU stay in patients with or suspected a Score a respiratory ≥ and a blood pressure ≤ mm When any two of these variables are the patient is qSOFA analysis used to support the recommendations of the on the of Sepsis identified qSOFA as a of poor in patients with or suspected infection, but no analysis was to support its use as a screening tool that time studies have the use of the qSOFA as a screening tool for sepsis The have been as to its have that qSOFA is more specific but than having two of SIRS for early identification of infection induced organ dysfunction SIRS qSOFA are screening tools for sepsis and the clinician to the of In the that of patients a qSOFA score 2 or but these patients for of poor have been when against the National Early Score and the Modified Early Score (MEWS) the presence of a qSOFA should the clinician to the of sepsis in all given the poor sensitivity of the the a strong recommendation against its use as a screening -

Importance: Abnormal peripheral perfusion after septic shock resuscitation has been associated with organ dysfunction and mortality. The potential role of the clinical assessment of peripheral perfusion as a target during resuscitation in early septic shock has not been established. Objective: To determine if a peripheral perfusion-targeted resuscitation during early septic shock in adults is more effective than a lactate level-targeted resuscitation for reducing mortality. Design, Setting, and Participants: Multicenter, randomized trial conducted at 28 intensive care units in 5 countries. Four-hundred twenty-four patients with septic shock were included between March 2017 and March 2018. The last date of follow-up was June 12, 2018. Interventions: Patients were randomized to a step-by-step resuscitation protocol aimed at either normalizing capillary refill time (n = 212) or normalizing or decreasing lactate levels at rates greater than 20% per 2 hours (n = 212), during an 8-hour intervention period. Main Outcomes and Measures: The primary outcome was all-cause mortality at 28 days. Secondary outcomes were organ dysfunction at 72 hours after randomization, as assessed by Sequential Organ Failure Assessment (SOFA) score (range, 0 [best] to 24 [worst]); death within 90 days; mechanical ventilation-, renal replacement therapy-, and vasopressor-free days within 28 days; intensive care unit and hospital length of stay. Results: Among 424 patients randomized (mean age, 63 years; 226 [53%] women), 416 (98%) completed the trial. By day 28, 74 patients (34.9%) in the peripheral perfusion group and 92 patients (43.4%) in the lactate group had died (hazard ratio, 0.75 [95% CI, 0.55 to 1.02]; P = .06; risk difference, -8.5% [95% CI, -18.2% to 1.2%]). Peripheral perfusion-targeted resuscitation was associated with less organ dysfunction at 72 hours (mean SOFA score, 5.6 [SD, 4.3] vs 6.6 [SD, 4.7]; mean difference, -1.00 [95% CI, -1.97 to -0.02]; P = .045). There were no significant differences in the other 6 secondary outcomes. No protocol-related serious adverse reactions were confirmed. Conclusions and Relevance: Among patients with septic shock, a resuscitation strategy targeting normalization of capillary refill time, compared with a strategy targeting serum lactate levels, did not reduce all-cause 28-day mortality. Trial Registration: ClinicalTrials.gov Identifier: NCT03078712.

The Surviving Sepsis Campaign (SSC) International Guidelines for the Management of Sepsis and Septic Shock provide guidance on the care of hospitalized adult patients with (or at risk for) sepsis, based on systematic summary and assessment of relevant literature. This executive summary reviews the history, scope, methodology, and major recommendations of the guidelines, focusing on aspects that are new or different compared with the 2016 guidelines that were published in 2017. Full description of the guidelines process and recommendations are provided in the complete guidelines document. HISTORY AND SCOPE OF THE GUIDELINES The SSC first published guidelines for the management of severe sepsis and septic shock in 2004. Updates were published in 2008, 2012, and 2017. The guidelines are sponsored by the Society of Critical Care Medicine (SCCM) and the European Society of Intensive Care Medicine (ESICM), with methodological support by the Guidelines in Intensive Care Development and Evaluation (GUIDE) group, and endorsement by 24 additional societies. There is no funding from any industry partner. Panel membership, patient involvement, and conflict of interest management are discussed in the complete guidelines document. The guidelines provide recommendations on the management of sepsis, focusing on aspects of care specific to sepsis and limiting duplication with other guidelines wherever possible. It is not intended to replace clinical judgement, which must account for the unique circumstances of an individual patient. Following the recommendation of SCCM and ESICM, there are now separate guidelines for sepsis in children (1). The SSC also published separate guidelines specific to the management of COVID (2,3). The 2021 guidelines largely apply to high-resource settings but discuss applicability of the recommendations to lower-resource settings as data allow. The SSC also creates sepsis bundles (4) (a selected set of interventions or processes of care distilled from evidence-based practice guidelines) to facilitate quality improvement and implementation of guidelines recommendations. However, the bundles are developed via a separate process and published separately from the guidelines. Definitions The guidelines recognize sepsis as life-threatening organ dysfunction secondary to a dysregulated host response to infection consistent with the Sepsis-3 consensus definition (5). However, studies were not required to use a particular sepsis definition to be considered as relevant evidence for the guidelines. Question Development and Outcome Prioritization Guidelines questions were selected based on panel rating, clinical practice variability, and inclusion in prior SSC guidelines, and then assigned to one of six SSC adult guidelines working groups: screening and initial resuscitation; infection; hemodynamics; ventilation; additional therapies; and goals of care and long-term outcomes. Clinical practice variation was identified through a global survey of SCCM and ESICM members regarding their current practice and how it related to previous recommendations. All questions were structured in the Population, Intervention, Control, and Outcomes (PICO) format. For each question, relevant outcomes were enumerated and ranked prior to the literature search. Search Strategy and Evidence Summation Professional librarians drafted and executed the search strategy for each PICO question (or group of similar questions), with input from subgroup members. Only English language studies published before May 2019 were included (the lag was the result of the guideline review and approval process coupled with the COVID-19 pandemic). For PICO questions addressed in the 2016 guidelines, the search strategy was revised and updated. Reviewers in the systematic review team, with input from methodologists and experts, screened article titles and abstracts to identify the highest quality evidence, particularly recent randomized controlled trials and high-quality systematic reviews. When new or updated meta-analyses were required, relevant data were abstracted with emphasis on intention-to-treat data where possible and conventional meta-analytic techniques were used to produce pooled estimates. Quality of Evidence and Formulation of Recommendations Using the GRADE approach, methodologists and panelists assessed the quality of evidence for each PICO question as high, moderate, low, or very low. Using the Evidence-to-Decision (EtD) framework (6), each subgroup drafted preliminary recommendations for their assigned PICO questions. The EtD framework took into account not only the magnitude of effect and quality of evidence, but also patient values, resources and cost, equity, acceptability, and feasibility (6). The strength of each recommendation was informed by the quality of the evidence and other components of the EtD framework. Strong recommendations (signified by “we recommend”) reflect high confidence that the desirable effects of adhering to a recommendation clearly outweigh undesirable effects. Weak recommendations (signified by “we suggest”) indicate that desirable effects likely outweigh undesirable effects. Best practice statements (BPSs) reflect ungraded strong recommendations and are used sparingly when benefit or harm is unequivocal, but evidence is difficult to summarize or assess according to GRADE methodology (7). Voting Progress Preliminary recommendations were discussed during face-to-face meetings and revised based on panel feedback prior to electronic voting by panel members who had no conflicts of interest. The a priori threshold for acceptance was having votes cast by at least 75% of the panel and 80% agreement among those who cast a vote. Up to three rounds of voting were allowed per PICO question. RECOMMENDATIONS The recommendations of the SSC 2021 guidelines update are summarized in Table 1 of the full guidelines document. There are 93 total statements, which address screening and initial resuscitation (n = 10 statements), infection (n = 21), hemodynamics (n = 14), ventilation (n = 12), additional therapies (n = 16), and goals of care and long-term outcomes (n = 20). Of the 93 statements, 15 are strong (16%) and 54 are weak (58%) recommendations, 15 are best practice statements (16%), and 9 are statements declaring ‘no recommendation’ (10%). Of the 15 strong recommendations, all but one are based on moderate or high-quality evidence. Selected recommendations that are new or revised from the 2016 guidelines are shown in Table 1. TABLE 1. - Selected New and/or Revised Recommendations in the 2021 Surviving Sepsis Campaign International Guidelines for the Management of Sepsis and Septic Shock 2016 Recommendation 2021 Recommendation Rationale for Change We recommend that in the resuscitation from sepsis-induced hypoperfusion, at least 30 mL/kg of IV crystalloid fluid be given within the first 3 hours. 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. This panel downgraded this recommendation from a strong recommendation to a weak recommendation based on the low quality of the evidence. There are no prospective intervention studies comparing different volumes for initial resuscitation in sepsis or septic shock. However, a retrospective analysis of adults presenting to an emergency department with sepsis or septic shock showed that failure to receive 30mL/kg of crystalloid fluid therapy within 3 hours of sepsis onset was associated with higher in-hospital mortality (10). Furthermore, the average volume of fluid received pre-randomization the PROCESS (11), PROMISE (12), and ARISE (13) trials was in the range of 30 mL/kg, suggesting this fluid volume has been adopted in routine clinical practice (14). We suggest using either balanced crystalloids or saline for fluid resuscitation of patients with sepsis or septic shock. For adults with sepsis or septic shock, we suggest using balanced crystalloid instead of normal saline for resuscitation. There are many, increasingly recognized potential adverse effects of normal saline including hyperchloremic metabolic acidosis. A network meta-analysis showed in an indirect comparison that balanced fluids were associated with decreased mortality compared with saline (15). In the 2018 SMART single-center cluster-randomized RCT comparing saline to balance fluid, the pre-specified subgroup of patients admitted with sepsis experienced lower 30-day mortality when randomized to balanced fluids versus saline (OR, 0.90; 95% CI, 0.67, 0.94) (16). Not addressed 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. Prompt initiation of vasopressors is an integral component of septic shock management. Vasopressors have been traditionally administered via central venous access due to concerns of extravasation and local tissue injury and ischemia. However, placement of central venous access requires specialized expertise and is time consuming, potentially leading to delays in administration. A recent systematic review showed that peripheral administration of vasopressors is generally safe, particularly if infused distally to the antecubital fossa and for short periods of time (< 6 hr) (17, 18). Peripheral administration of vasopressors is associated with shorter time to administration and faster time to achieving a MAP > 65 mm Hg (19). Not addressed For adults with sepsis or septic shock we suggest against using IV vitamin C. A 2017 single center before and after study reported reduced mortality with administration of high-dose Vitamin C, hydrocortisone, and thiamine among patients with sepsis and sepsis shock (20). However, an updated meta-analysis by the guideline panel found no association between vitamin C and reduced mortality. We suggest against using IV hydrocortisone to treat patients with septic shock if adequate fluid resuscitation and vasopressor therapy can restore hemodynamic stability. If this is not achievable, we suggest IV hydrocortisone at a dose of 200 mg/day. For adults with septic shock and an ongoing requirement for vasopressor therapy we suggest using IVcorticosteroids. Since the 2016 guideline, three large RCTs have been published (21–23). An updated meta-analysis found systemic corticosteroid to accelerate resolution of shock (MD, 1.52 days; 95% CI, 1.71 to 1.32) and increase vasopressor-free days (MD, 1.5 days; 95% CI, 0.8 to 3.11 days) (24). However, corticosteroid use increased neuromuscular weakness (RR, 1.21; 95% CI, 1.01 to 1.45), without a clear effect on short- or long-term mortality (24). The overall quality of evidence was moderate. The panel judged the desirable effects (shock resolution, vasopressor-free days) to outweigh the undesirable effects. This observation, combined with consideration of the resources required, cost of the intervention, and feasibility supported a weak recommendation in favor of using low-dose corticosteroid therapy in septic shock. Not addressed For adult survivors of sepsis or septic shock, we recommend assessment and follow-up for physical, cognitive, and emotional problems after hospital discharge. Given the prevalence of new and worsening physical, cognitive, and emotional problems experienced by sepsis survivors, we recommend assessment and follow-up of these problems after discharge. Screening and Initial Resuscitation The guidelines recommend that hospitals use a performance improvement program for sepsis, including screening of high-risk patients and standard operating procedures for management. The guidelines recognize sepsis as a medical emergency and recommend that treatment and resuscitation begin immediately. For initial resuscitation in patients with sepsis-induced hypoperfusion or septic shock, the guidelines suggest 30 mL/kg IV crystalloid. This recommendation was downgraded from a strong recommendation to a weak recommendation based on the low quality of evidence. Additionally, the guidelines suggest resuscitation be guided by dynamic over static measures, target a decrease in serum lactate, and use capillary refill as an adjunct measure of perfusion. New to this update, the guidelines recommend against qSOFA as a sole screening tool and suggest that patients who are determined to need intensive care be admitted to an ICU within 6 hours. Infection As in the 2016 guidelines, the 2021 guidelines again recommend delivering antimicrobials as soon as possible, ideally within 1 hour of sepsis recognition. The 2021 guidelines provide additional guidance on initiation of antimicrobials, recognizing the challenge of diagnostic uncertainty early in a patient’s presentation. The guidelines now stratify antimicrobial timing recommendations based on the likelihood of sepsis and presence of shock (Figure 1). For patients with probable sepsis or with shock resulting from possible or probable sepsis, the guidelines recommend administering antimicrobials immediately, ideally within 1 hour of recognition. For patients with possible sepsis but without shock, the guidelines recommend rapid assessment of the likelihood of infection versus non-infectious illness. If concern for infection persists after a time-limited course of rapid investigation, then antimicrobials should be administered within 3 hours from when sepsis was first recognized. Finally, for patients with a low likelihood of infection and without shock, the guidelines suggest deferring antimicrobials while continuing to closely monitor the patient.Figure 1.: 2021 Recommendations of the initiation of antimicrobials.The guidelines include several additional recommendations regarding antimicrobial therapy for sepsis. Given the heterogeneity of infectious pathogens, sites of infection, severity of illness, local resistance patterns, and other patient and contextual factors, specific treatment recommendations are beyond the scope of the guidelines. However, the guidelines provide a framework for approaching antimicrobial therapy. They suggest that use of empiric coverage for methicillin-resistant Staphylococcus aureus (MRSA), empiric double-coverage for gram-negative pathogens, and empiric coverage for fungal pathogens be determined based on patient and contextual risk factors. The guidelines provide several recommendations for optimizing antibiotic dosing, addressing source control, and determining duration of antimicrobial therapy. Hemodynamics The guidelines recommend crystalloid fluids as a first line for resuscitation, and new in this update, suggest balanced crystalloids over normal saline. For patients with septic shock, the guidelines recommend norepinephrine as the first-line vasopressor and suggest that vasopressors be started peripherally to avoid delays in administration in the absence of central venous access. There was insufficient evidence to make a recommendation regarding the use of a restrictive versus liberal fluid strategy after the initial fluid resuscitation, and this remains an important area for future research. As in the 2016 guidelines, albumin is suggested in patients who have received large volumes of crystalloid. Ventilation The guidelines recommend a low tidal volume ventilation strategy with limitation of plateau pressure for patients with sepsis-associated ARDS and the use of prone positioning in moderate-to-severe ARDS, and suggest a low tidal volume approach for all patients with sepsis-induced respiratory failure. The guidelines suggest using traditional recruitment maneuvers but recommend against an incremental PEEP strategy. There was insufficient evidence to make a recommendation regarding use of liberal versus conservative oxygen targets; this remains an important area for future research. Additional Therapies To limit overlap with other guidelines and create space for a new section focused on long-term outcomes, PICOs on additional therapies were reduced from prior SSC guidelines. However, there are some noteworthy new recommendations regarding adjunctive therapies. In contrast to the 2016 guidelines, the 2021 guidelines suggest the use of IV corticosteroids for patients with an ongoing need for vasopressor therapy based on newer clinical trial data. Additionally, the guidelines suggest against using IV vitamin C for sepsis or septic shock based on recent randomized controlled trials and an updated meta-analysis showing no impact on mortality. Goals of Care and Long-Term Outcomes As acute survival from sepsis has improved, a growing number of sepsis survivors leave the hospital alive—many of whom experience long-term morbidity and a heightened risk for adverse health outcomes including mortality in the months and years following sepsis (8). Indeed, the 2017 World Health Organization resolution on sepsis called for improving outcomes of sepsis survivors and addressing survivors’ access to rehabilitation (9). Given the burden of long-term morbidity and mortality stemming from sepsis, the SSC guidelines now include a section dedicated to the longer-term recovery from sepsis. To enhance recovery, the guidelines recommend screening for economic and social support for patient and families, involving patients and families in shared decision-making regarding discharge planning, reconciling medications at both ICU and hospital discharge, including information about sepsis and common impairment after sepsis in the discharge summary, and assessing for physical, cognitive, and emotional problems after hospital discharge. The guidelines suggest having a critical care transitional program during ICU stay to floor transitions, using a handoff process during transitions of care, offering verbal and written sepsis education, and referring patients to peer support programs, post-critical illness follow-up programs (if available), and post-hospital rehabilitation programs (for selected survivors). There was insufficient evidence to make a recommendation regarding early cognitive rehabilitation or timing of post-hospital follow up. While many of these recommendations are generally applicable to critically ill and hospitalized patients, the panel deemed them necessary to include in the sepsis guidelines given the burden of long-term morbidity and mortality due to sepsis. CONCLUSIONS This executive summary highlights the most novel aspects of the Surviving Sepsis Campaign International Guidelines for the Management of Sepsis and Septic Shock 2021 that clinicians and stakeholders should consider when caring for adult patients with (or at risk for) sepsis. The recommendation rationales, informed by rigorous data evaluation, discussion by panelists, and input from patients, provide deeper insight into each recommendation. We believe that the 2021 SSC guidelines will foster the delivery of best practices for sepsis evaluation and management, as well as highlight aspects of management where additional evidence is needed most urgently.

INTRODUCTION: Our goal was to assess the effects of titration of a norepinephrine infusion to increasing levels of mean arterial pressure (MAP) on sublingual microcirculation. METHODS: Twenty septic shock patients were prospectively studied in two teaching intensive care units. The patients were mechanically ventilated and required norepinephrine to maintain a mean arterial pressure (MAP) of 65 mmHg. We measured systemic hemodynamics, oxygen transport and consumption (DO2 and VO2), lactate, albumin-corrected anion gap, and gastric intramucosal-arterial PCO2 difference (DeltaPCO2). Sublingual microcirculation was evaluated by sidestream darkfield (SDF) imaging. After basal measurements at a MAP of 65 mmHg, norepinephrine was titrated to reach a MAP of 75 mmHg, and then to 85 mmHg. Data were analyzed using repeated measurements ANOVA and Dunnett test. Linear trends between the different variables and increasing levels of MAP were calculated. RESULTS: Increasing doses of norepinephrine reached the target values of MAP. The cardiac index, pulmonary pressures, systemic vascular resistance, and left and right ventricular stroke work indexes increased as norepinephrine infusion was augmented. Heart rate, DO2 and VO2, lactate, albumin-corrected anion gap, and DeltaPCO2 remained unchanged. There were no changes in sublingual capillary microvascular flow index (2.1 +/- 0.7, 2.2 +/- 0.7, 2.0 +/- 0.8) and the percent of perfused capillaries (72 +/- 26, 71 +/- 27, 67 +/- 32%) for MAP values of 65, 75, and 85 mmHg, respectively. There was, however, a trend to decreased capillary perfused density (18 +/- 10,17 +/- 10,14 +/- 2 vessels/mm2, respectively, ANOVA P = 0.09, linear trend P = 0.045). In addition, the changes of perfused capillary density at increasing MAP were inversely correlated with the basal perfused capillary density (R2 = 0.95, P < 0.0001). CONCLUSIONS: Patients with septic shock showed severe sublingual microcirculatory alterations that failed to improve with the increases in MAP with norepinephrine. Nevertheless, there was a considerable interindividual variation. Our results suggest that the increase in MAP above 65 mmHg is not an adequate approach to improve microcirculatory perfusion and might be harmful in some patients.