Surviving Sepsis Campaign: 2021 Updates

Author: Brit Long, MD (@long_brit) // Reviewed by: Alex Koyfman, MD (@EMHighAK)

The Surviving Sepsis Campaign published updated guidelines for the management of sepsis and septic shock, with 93 recommendations. We will not cover all 93 here. Instead, we will break this post into the EM Top Changes, with some discussion of the literature behind these changes, as well as other changes that impact our practice.

EM Top Changes:

• 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.
  • The ANDROMEDA SHOCK trial evaluated resuscitation using capillary refill time and found it to be more effective than a resuscitation strategy using lactate in reducing organ dysfunction (1).
• 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.
  • This is a change from “recommended” due to low quality of evidence. There are no prospective interventional studies looking at different volumes for the initial resuscitation of those with sepsis or septic shock. A retrospective study including ED adult patients with sepsis or septic shock found failure to receive 30 mL/kg of crystalloids was associated with higher mortality (2). Guidelines also cite the PROCESS, PROMISE, and ARISE trials, which provided fluid in the 30 mL/kg range (3-5).
• 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.
  • Normal saline may result in hyperchloremic metabolic acidosis. The SMART and SALT ED trials support the use of balanced crystalloids, with a network meta-analysis demonstrating decreased mortality with balanced fluids (6-8).
• 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.
  • An RCT evaluating patients in septic shock randomized to MAP targets of 65-70 mm Hg versus 80-85 mm Hg found no difference in mortality. There was reduced risk of renal replacement therapy in patients with chronic hypertension and higher rates of atrial fibrillation in the group randomized to the higher MAP target group (9).
• For adults with septic shock, we suggest starting vasopressors peripherally to restore mean arterial pressure rather than delaying initiation until central venous access is secured. Weak, very low quality of evidence, NEW.
  • Vasopressors play an important role in treatment of septic shock. Peripheral administration of vasopressors is generally safe if infused in the antecubital fossa for a short period of time (< 6 hours) (10,11). Peripheral infusion is associated with shorter time to administration and time to achieving a MAP > 65 (12).
• For adults with sepsis-induced hypoxemic respiratory failure, we suggest the use of high flow nasal oxygen (also known as HFNC) over noninvasive ventilation (NIV). Weak, low quality of evidence, NEW.
  • One RCT demonstrates improved 90-day survival with HFNC compared with NIV (OR 0.42, 95% CI 0.21-0.85), with more days from mechanical ventilation (13). In another study including those with severe hypoxemia, HFNC was resulted in lowered rates of intubation when compared with conventional oxygen therapy (14-16).
• For adults with sepsis or septic shock we suggest against using IV vitamin C. Weak, low quality of evidence, NEW.
  • One before and after study published in 2017 reported reduced mortality with vitamin C, thiamine, and hydrocortisone (17). However, the VITAMINS trial found no impact on mortality with this regimen (18), and a meta-analysis evaluating high dose vitamin C also found no mortality impact (19).
• 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.
  • Since the 2016 guidelines, several large RCTs have been published, with a meta-analysis finding faster resolution of shock and increased vasopressor-free days in those receiving systemic steroids (20-23). However, steroids are associated with increased neuromuscular weakness and have no clear effect on mortality (23).

The Rest:

• 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.
• For adults suspected of having sepsis, we suggest measuring blood lactate. Weak, low quality of evidence.
• Sepsis and septic shock are medical emergencies, and we recommend that treatment and resuscitation begin immediately. Best practice statement.
• 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.
• 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.
• For adults with sepsis or septic shock, we recommend using crystalloids as first-line fluid for resuscitation. Strong, moderate-quality evidence.
• For adults with sepsis or septic shock, we suggest using albumin in patients who received large volumes of crystalloids. Weak, moderate-quality evidence.
• 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.
• 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.
• 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.
• For adults with septic shock and inadequate mean arterial pressure levels despite norepinephrine and vasopressin, we suggest adding epinephrine. Weak, low quality of evidence.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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 make no recommendation on the use of antiviral agents. No recommendation.
• 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.
• 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.
• 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.
• 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.
• 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.
• For adults with moderate to severe sepsis induced ARDS, we suggest using higher PEEP over lower PEEP. Weak, moderate-quality evidence.
• 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.
• For adults with sepsis or septic shock we recommend using a restrictive (over liberal) transfusion strategy. Strong, moderate-quality evidence.
• For adults with sepsis or septic shock we suggest against using IV immunoglobulins. Weak, low quality of evidence.
• 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.
• 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.
• For adult survivors of sepsis or septic shock, we recommend assessment and follow-up for physical, cognitive, and emotional problems after hospital discharge.

The Guidelines:

• Evans L, Rhodes A, Alhazzani W, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021. Crit Care Med. 2021 Nov 1;49(11):e1063-e1143.
• Evans L, Rhodes A, Alhazzani W, et al. Executive Summary: Surviving Sepsis Campaign: International Guidelines for the Management of Sepsis and Septic Shock 2021. Crit Care Med. 2021 Nov 1;49(11):1974-1982.

References:

1. Hernandez G, Ospina-Tascon GA, Damiani LP, et al; The ANDROMEDA SHOCK Investigators and the Latin America Intensive Care Network (LIVEN). Effect of a resuscitation strategy targeting peripheral perfusion status vs serum lactate levels on 28-day mortality among patients with septic shock: The ANDROMEDA-SHOCK randomized clinical trial. JAMA 2019; 321:654–664.
2. Kuttab HI, Lykins JD, Hughes MD, et al. Evaluation and Predictors of Fluid Resuscitation in Patients With Severe Sepsis and Septic Shock. Crit Care Med 2019; 47:1582–1590.
3. Yealy DM, Kellum JA, Huang DT, et al; ProCESS Investigators. A randomized trial of protocol-based care for early septic shock. N Engl J Med 2014; 370:1683–1693.
4. Investigators A, Group ACT, Peake SL, et al. Goal-directed resuscitation for patients with early septic shock. N Engl J Med 2014; 371:1496−1506.
5. Mouncey PR, Osborn TM, Power GS, et al; ProMISe Trial Investigators. Trial of early, goal-directed resuscitation for septic shock. N Engl J Med 2015; 372:1301–1311.
6. Semler MW, Self WH, Wanderer JP, et al; SMART Investigators and the Pragmatic Critical Care Research Group. Balanced Crystalloids versus Saline in Critically Ill Adults. N Engl J Med. 2018 Mar 1;378(9):829-839.
7. Self WH, Semler MW, Wanderer JP, et al; SALT-ED Investigators. Balanced Crystalloids versus Saline in Noncritically Ill Adults. N Engl J Med. 2018 Mar 1;378(9):819-828.
8. Rochwerg B, Alhazzani W, Sindi A, et al. Fluids in Sepsis and Septic Shock Group: Fluid resuscitation in sepsis: a systematic review and network meta-analysis. Ann Intern Med 2014; 161:347–355.
9. Asfar P, Meziani F, Hamel JF, et al; SEPSISPAM Investigators. High versus low blood-pressure target in patients with septic shock. N Engl J Med 2014; 370:1583–1593.
10. Tian DH, Smyth C, Keijzers G, et al. Safety of peripheral administration of vasopressor medications: A systematic review. Emerg Med Australas 2020; 32:220–227.
11. Loubani OM, Green RS. A systematic review of extravasation and local tissue injury from administration of vasopressors through peripheral intravenous catheters and central venous catheters. J Crit Care 2015; 30:653.e9–653.17.
12. Delaney A, Finnis M, Bellomo R, et al. Initiation of vasopressor infusions via peripheral versus central access in patients with early septic shock: A retrospective cohort study. Emerg Med Australas 2020; 32:210–219.
13. Frat JP, Thille AW, Mercat A, et al. FLORALI Study Group; REVA Network: High-flow oxygen through nasal cannula in acute hypoxemic respiratory failure. N Engl J Med 2015; 372:2185–2196.
14. Ni YN, Luo J, Yu H, et al. The effect of high-flow nasal cannula in reducing the mortality and the rate of endotracheal intubation when used before mechanical ventilation compared with conventional oxygen therapy and noninvasive positive pressure ventilation. A systematic review and metaanalysis. Am J Emerg Med 2018; 36:226–233.
15. Ou X, Hua Y, Liu J, et al. Effect of high-flow nasal cannula oxygen therapy in adults with acute hypoxemic respiratory failure: A meta-analysis of randomized controlled trials. CMAJ 2017; 189:E260–E267.
16. Rochwerg B, Granton D, Wang DX, et al. High-flow nasal cannula compared with conventional oxygen therapy for acute hypoxemic respiratory failure: Author’s reply. Intensive Care Med 2019; 45:1171.
17. Marik PE, Khangoora V, Rivera R, et al. Hydrocortisone, Vitamin C, and Thiamine for the Treatment of Severe Sepsis and Septic Shock: A Retrospective Before-After Study. Chest 2017; 151:1229–1238.
18. Fujii T, Luethi N, Young PJ, et al; VITAMINS Trial Investigators. Effect of Vitamin C, Hydrocortisone, and Thiamine vs Hydrocortisone Alone on Time Alive and Free of Vasopressor Support Among Patients With Septic Shock: The VITAMINS Randomized Clinical Trial. JAMA. 2020 Feb 4;323(5):423-431.
19. Sato R, Hasegawa D, Prasitlumkum N, et al. Effect of IV High-Dose Vitamin C on Mortality in Patients With Sepsis: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Crit Care Med. 2021 Dec 1;49(12):2121-2130.
20. Annane D, Renault A, Brun-Buisson C, et al; CRICSTRIGGERSEP Network. Hydrocortisone plus Fludrocortisone for Adults with Septic Shock. N Engl J Med 2018;378:809–818.
21. Venkatesh B, Finfer S, Cohen J, et al. Adjunctive Glucocorticoid Therapy in Patients with Septic Shock. N Engl J Med 2018; 378:797−808.
22. Gordon AC, Mason AJ, Thirunavukkarasu N, et al; VANISH Investigators. Effect of Early Vasopressin vs Norepinephrine on Kidney Failure in Patients With Septic Shock: The VANISH Randomized Clinical Trial. JAMA 2016; 316:509–518.
23. Rygad SL, Butler E, Granholm A, et al. Low-dose corticosteroids for adult patients with septic shock: a systematic review with meta-analysis and trial sequential analysis. Intensive Care Med 2018; 44:1003–1016.