Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021

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11/06/2021

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.

KEY WORDS: adults; evidence-based medicine; guidelines; sepsis; septic shock

INTRODUCTION

Sepsis is life-threatening organ dysfunction caused by a dysregulated host re- sponse 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 guid- ance for the clinician caring for adult patients with sepsis or septic shock in the hospital setting. Recommendations from these guidelines cannot re- place the clinician’s decision-making capability when presented with a unique patient’s clinical variables. These guidelines are intended to reflect best prac- tice (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

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 as- sociated 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

Laura Evans1 Andrew Rhodes2 Waleed Alhazzani3 Massimo Antonelli4 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

Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021

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.

LWW

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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 re- cord (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) crite- ria, 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 pre- dicting 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 sensi- tivity and specificity of sepsis screening tools, they are an important compo- nent 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 retro- spective 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-analy- sis 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.

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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 rec-

ommend using a performance improvement program for sepsis, including sepsis screening for acutely ill, high-risk patients and standard op- erating procedures for treatment.

Strong, moderate-quality evidence (for screening)

Changed from Best practice statement

“We recommend that hospi- tals and hospital systems have a performance improvement pro- gram for sepsis including sepsis screening for acutely ill, high-risk patients.”

Strong, very low-quality evidence (for standard operating proce- dures)

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 sug-

gest measuring blood lactate. Weak, low quality of evidence INITIAL RESUSCITATION

4. Sepsis and septic shock are medical emergen- cies, 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 resus- citation.

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 sug- gest 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 sug- gest 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 re- quire ICU admission, we suggest admitting the patients to the ICU within 6 hr.

Weak, low quality of evidence

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INFECTION

11. For adults with suspected sepsis or septic shock but unconfirmed infection, we recom- mend 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 adminis- tering antimicrobials immediately, ideally within 1 hr of recognition.

Strong, low quality of evidence (Septic shock)

CHANGED from previous:

“We recommend that administra- tion of intravenous antimicrobials should be initiated as soon as pos- sible after recognition and within one hour for both a) septic shock and b) sepsis without shock”

Strong, very low quality of evi- dence (Sepsis without shock)

strong recommendation, mod- erate quality of evidence

13. For adults with possible sepsis without shock, we recommend rapid assessment of the likeli- hood 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 inves- tigation 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 recogni- tion and within 1 hr for both a) septic shock and b) sepsis without shock”

strong recommendation, mod- erate quality of evidence

15. For adults with a low likelihood of infection and without shock, we suggest deferring anti- microbials 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 recogni- tion and within 1 hr for both a) septic shock and b) sepsis without shock“

strong recommendation, mod- erate quality of evidence

16. For adults with suspected sepsis or septic shock, we suggest against using procalcitonin plus clin- ical evaluation to decide when to start antimicrobi- als, 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, mod- erate quality of evidence

Recommendations 2021 Recommendation Strength

and Quality of Evidence Changes From 2016 Recommendations

(5)

18. For adults with sepsis or septic shock at low risk of MRSA, we suggest against using em- piric 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, mod- erate quality of evidence

19. For adults with sepsis or septic shock and high risk for multidrug resistant (MDR) organ- isms, 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 bac- terial 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 em- piric 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 sug- gest using prolonged infusion of beta-lactams for maintenance (after an initial bolus) over conventional bolus infusion.

Weak, moderate-quality evidence Recommendations 2021 Recommendation Strength

and Quality of Evidence Changes From 2016 Recommendations

(6)

26. For adults with sepsis or septic shock, we recommend optimising dosing strategies of antimicrobials based on accepted pharmaco- kinetic/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 imple- menting 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 sug- gest daily assessment for de-escalation of anti- microbials 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 rec- ommend 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 bal- anced crystalloids or saline for fluid resuscitation of patients with sepsis or septic shock”

34. For adults with sepsis or septic shock, we sug- gest 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 Recommendations 2021 Recommendation Strength

and Quality of Evidence Changes From 2016 Recommendations

(7)

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 resuscitat- ing 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 norepi- nephrine 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 dys-

function with persistent hypoperfusion despite adequate volume status and arterial blood pressure, we suggest either adding dobuta- mine to norepinephrine or using epinephrine alone.

Weak, low quality of evidence

42. For adults with septic shock and cardiac dys- function with persistent hypoperfusion despite adequate volume status and arterial blood pres- sure, we suggest against using levosimendan.

Weak, low quality of evidence NEW

43. For adults with septic shock, we suggest inva- sive 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 start- ing 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 Recommendations 2021 Recommendation Strength

and Quality of Evidence Changes From 2016 Recommendations

(8)

45. There is insufficient evidence to make a rec- ommendation on the use of restrictive versus liberal fluid strategies in the first 24 hr of re- suscitation in patients with sepsis and septic shock who still have signs of hypoperfusion and volume depletion after the initial resusci- tation.

No recommendation NEW

“We suggest using either bal- anced 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 resuscitat- ing patients with sepsis or septic shock.”

Weak recommendation, low quality of evidence

VENTILATION

46. There is insufficient evidence to make a recom- mendation on the use of conservative oxygen targets in adults with sepsis-induced hypox- emic respiratory failure.

No recommendation

47. For adults with sepsis-induced hypoxemic res- piratory 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- mendation on the use of noninvasive ventila- tion in comparison to invasive ventilation for adults with sepsis-induced hypoxemic respira- tory failure.

No recommendation

49. For adults with sepsis-induced ARDS, we rec- ommend 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 rec- ommend 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

Recommendations 2021 Recommendation Strength

and Quality of Evidence Changes From 2016 Recommendations

(9)

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 sug- gest 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 he- modynamic 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-

gest against using polymyxin B hemoperfusion. Weak, low quality of evidence NEW from previous:

“We make no recommendation regarding the use of blood puri- fication techniques”

60. There is insufficient evidence to make a recom- mendation on the use of other blood purifica- tion 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 pro- phylaxis.

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 rec- ommend using low molecular weight heparin over unfractionated heparin for VTE prophy- laxis

Strong, moderate-quality evidence

66. For adults with sepsis or septic shock, we suggest against using mechanical VTE prophy- laxis, in addition to pharmacological prophy- laxis, over pharmacologic prophylaxis alone.

Weak, low quality of evidence Recommendations 2021 Recommendation Strength

and Quality of Evidence Changes From 2016 Recommendations

(10)

67. In adults with sepsis or septic shock and AKI, we suggest using either continuous or intermit- tent renal replacement therapy.

Weak, low quality of evidence

68. In adults with sepsis or septic shock and AKI, with no definitive indications for renal replace- ment therapy, we suggest against using renal replacement therapy.

Weak, moderate-quality evidence

69. For adults with sepsis or septic shock, we rec- ommend 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 hypoper-

fusion-induced lactic acidemia, we suggest against using sodium bicarbonate therapy to improve hemodynamics or to reduce vaso- pressor 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 recommenda- tion on any specific standardized criterion to trigger goals of care discussion.

No recommendation

77. For adults with sepsis or septic shock, we rec- ommend that the principles of palliative care (which may include palliative care

consultation based on clinician judgement) be integrated into the treatment plan, when appro- priate, 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 Recommendations 2021 Recommendation Strength

and Quality of Evidence Changes From 2016 Recommendations

(11)

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 recommen- dation 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 ec- onomic 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 dis- charge 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 Recommendations 2021 Recommendation Strength

and Quality of Evidence Changes From 2016 Recommendations

(12)

Rationale

The qSOFA uses three variables to predict death and prolonged ICU stay in patients with known or sus- pected sepsis: a Glasgow Coma Score < 15, a respira- tory 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 rec- ommendations 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 per- formed to support its use as a screening tool (5). Since that time numerous studies have investigated the po- tential 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 cli- nician needs to understand the limitations of each. In the original derivation study, authors found that only

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 compar- ing 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.

Rationale

The association of lactate level with mortality in patients with suspected infection and sepsis is well established (45, 46). Its use is currently recom- mended as part of the SSC Hour-1 sepsis bundle for those patients with sepsis (47, 48), and an elevated

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 recom- mendation 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 rehabili- tation program.

Weak, very low quality of evidence

Recommendation

3. For adults suspected of having sepsis, we suggest measuring blood lactate.

Weak recommendation, low-quality evidence.

Recommendations 2021 Recommendation Strength

and Quality of Evidence Changes From 2016 Recommendations

(13)

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 clini- cally suspected (but not confirmed) sepsis. Several studies have assessed the use of lactate in this con- text (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 measure- ments at presentation and reduced mortality; how- ever, 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 nei- ther sensitive nor specific enough to rule-in or rule- out the diagnosis on its own. Lactate testing may not be readily available in many resource-limited set- tings (54–61). Therefore, we issued a weak recom- mendation 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

Rationale

Timely, effective fluid resuscitation is crucial for the stabilization of sepsis-induced tissue hypoperfusion in sepsis and septic shock. Previous guidelines rec- ommend initiating appropriate resuscitation imme- diately 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 ob- servational evidence (62). There are no prospective intervention studies comparing different volumes for initial resuscitation in sepsis or septic shock. A ret- rospective analysis of adults presenting to an emer- gency 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) tri- als, the average volume of fluid received pre-random- ization 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 adminis- tration following initial resuscitation. Such admin- istration needs to be balanced with the risk of fluid

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.

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 cap- illary refill time to guide resuscitation as an adjunct to other measures of perfusion.

Weak recommendation, low-quality evidence.

(14)

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 intravas- cular volume status and organ perfusion. Heart rate, central venous pressure (CVP) and systolic blood pres- sure alone are poor indicators of fluid status. Dynamic measures have demonstrated better diagnostic accu- racy at predicting fluid responsiveness compared with static techniques. Dynamic measures include passive leg raising combined with cardiac output (CO) meas- urement, 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 differ- ence in mortality between septic patients resuscitated with a volume responsiveness-guided approach com- pared 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 associ- ated 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 admin- istration 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 sensi- tivity of detecting fluid responders and nonresponders based on measurement of CO (70). In resource-limited

regions where measurement of CO or SV may not be possible, a >15% increase in pulse pressure could indi- cate that the patient is fluid responsive utilizing a pas- sive 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 cel- lular 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-anal- yses 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, lac- tate 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 extremi- ties, 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 target- ing CRT normalization was more effective than a resus- citation 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 sig- nificantly 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 care- ful, frequent, and comprehensive patient evaluation to predict or recognize fluid overload early, particularly

(15)

where critical care resources are constrained. Relevant consideration of the background pathology or patho- logical processes pertinent to the patient should also inform management (69, 78).

Mean Arterial Pressure

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 auto- regulate blood flow, MAPs below a threshold, usually understood to be approximately 60 mm Hg, are asso- ciated with decreased organ perfusion, which tracks linearly with MAP (79). Previous SSC guidelines rec- ommended 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 hy- pertension. Additionally, targeting higher MAP with vasopressors was associated with a higher risk of atrial fibrillation. A limitation of this study was that the av- erage 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 hy- potension” (MAP 60–65 mm Hg) group with a “usual care” group that received vasopressors and MAP tar- gets set by the treating physician in patients aged 65 years and older with septic shock (82, 83). The inter- vention group in this study achieved a mean MAP of 66.7 mm Hg, compared with 72.6 mm Hg in the usual

care group. Among 2,463 analyzed patients, there was significantly less exposure to vasopressors in the inter- vention group, measured by duration of vasopressor infusion and total vasopressor doses expressed in nor- epinephrine 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 ini- tial resuscitation of patients with septic shock who re- quire vasopressors.

Admission to Intensive Care

Rationale

The outcome of critically ill patients depends on timely application of critical care interventions in an appro- priate 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 ret- rospective 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 as- sociated 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 admit- ted to 120 US ICUs (87). Mortality increased when ED stay exceeded 6 hours (17% vs 12.9%, p < 0.001).

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.

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.

(16)

Among hospital survivors, the delayed admission group had a longer hospital stay, higher mortality, and higher rates of mechanical ventilation and central ve- nous 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 pa- tient flow and improved staff morale (89). However, al- though 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

Rationale

In previous versions of these guidelines, we high- lighted the importance of obtaining a full screen for infectious agents prior to starting antimicrobials wher- ever 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 antimicro- bial 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).

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 dys- function. Indeed, a third or more of patients initially diagnosed with sepsis turn out to have noninfectious conditions (90, 93, 94). Best practice is to continu- ally assess the patient to determine if other diagnoses are more or less likely, especially because a patient’s clinical trajectory can evolve significantly after hos- pital admission, increasing or decreasing the likeli- hood 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 pa- tient 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 or- ders, electronic prompts, or mandatory check lists all seem useful in theory, but each has disadvantages in terms of provider acceptance or assuring that provid- ers thoughtfully assess the need for antibiotics rather than checking a box in the electronic record or reflex- ively 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 syn- drome that does not benefit from antimicrobials) is demonstrated or strongly suspected. Since this sit- uation is not always apparent, continued reassess- ment 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

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.

Recommendations

12. For adults with possible septic shock or a high like- lihood 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)

Figure

Updating...

References

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