By Kathryn Radigan, MD, MSCI
Attending Physician, Division of Pulmonary and Critical Care, Stroger Hospital of Cook County, Chicago
Sepsis is defined as a dysregulated immune response producing life-threatening organ dysfunction. It remains the leading cause of death in U.S. hospitals, contributing to one in every two to three deaths.1,2 Similar to acute stroke and acute myocardial infarction, early identification and optimal management of sepsis improve outcomes.
History
The Surviving Sepsis Campaign (SSC) started in 2002 through a collaboration between the Society of Critical Care Medicine and the European Society of Intensive Care Medicine.3 The SSC was committed to reducing mortality and morbidity from sepsis and septic shock worldwide. The SSC advanced these efforts further in 2004 by drafting guidelines for the management of severe sepsis and septic shock, which were updated in 2008, 2012, 2016, and most recently in 2021.
Surviving Sepsis Campaign Guidelines
Prior to 2016, strict early goal-directed therapy (EGDT) targets were emphasized. Subsequent revisions highlighted the need for early, appropriate antibiotics along with a new focus on initial resuscitation, stressing the importance of dynamic measurements instead of static variables to predict fluid responsiveness.4,5 The goal was to transition from a protocolized, quantitative resuscitation strategy to an approach that was more patient-centered and guided by hemodynamic assessment. Unfortunately, fluids often were continued without re-evaluating the patient or when no clinical benefit had been shown.6 The most recent 2021 revisions continue to stress the importance of these ideals, but they also place an increased emphasis on the hour-1 bundle and improving the care of sepsis patients after they are discharged from the intensive care unit (ICU).7
Screening and Initial Resuscitation
The first recommendation listed in the 2021 guidelines advises hospitals to use a performance improvement program for sepsis, including screening acutely ill, high-risk patients and having standard operating procedures for management.8 The guidelines identify sepsis as a medical emergency, with recommendations that treatment and resuscitation start immediately with admission to the ICU within six hours. Since early identification is paramount, the guidelines recommend against quick Sequential Organ Failure Assessment (qSOFA) compared to Systemic Inflammatory Response Syndrome (SIRS), National Early Warning Score (NEWS), or Modified Early Warning Score (MEWS) as a sole screening tool. Although the presence of a positive qSOFA should alert the clinician to the possibility of sepsis in all resource settings, it should not be used as a single screening tool given its poor sensitivity.9
In patients with sepsis-induced hypoperfusion or septic shock, the guidelines suggest initial resuscitation with 30 mL/kg of intravenous (IV) crystalloid.8 This recommendation was downgraded from a strong to a weak recommendation because of low quality of evidence. Using pooled data from the PROCESS, ARISE, and PROMISE trials to determine the effect of EGDT vs. usual care, PRISM investigators found that EGDT patients received 27.5 mL/kg of fluid compared to usual care patients who received 27.7 mL/kg of fluid.10 The recommendation is not without controversy; another retrospective cohort study showed that failure to reach 30 mL/kg by three hours was associated with increased odds of in-hospital mortality, irrespective of comorbidities.11,12 Additionally, the guidelines highlight that resuscitation be guided by dynamic rather than static measures, target a decrease in serum lactate, and use capillary refill as an adjunct measure of perfusion.8,13,14
Infection
As in the 2016 guidelines, the 2021 guidelines advise administering antimicrobials urgently, ideally within one hour of sepsis recognition.8 Inadequately dosed or delayed antibiotics have been found to increase mortality nearly 8% per hour during the first six hours after sepsis is diagnosed, supporting the idea that there may be a “golden hour” of antibiotic administration.15,16 The updated guidelines provide more detailed guidance about antimicrobial initiation, noting that the uncertainty of diagnosis is a challenge and stratifying the timing recommendations of antimicrobials based on the likelihood of sepsis and the presence or absence of shock.8
For patients with probable sepsis or with shock resulting from possible or probable sepsis, the guidelines recommend giving antimicrobials immediately, ideally within one hour of recognition. For patients with possible sepsis but without shock, the guidelines recommend an urgent assessment of the likelihood of infection vs. a noninfectious illness. A history and clinical examination, tests for infectious and noninfectious causes of acute illness, and immediate treatment of acute conditions are included in the rapid assessment. If there remains concern for infection after a time-limited course of expedited investigation, then antimicrobials should be given within three hours from when sepsis was first recognized. For patients who have a low likelihood of infection and without shock, the guidelines suggest that antimicrobials can be deferred while the patient continues to receive close monitoring.
Guidelines also suggest carefully evaluating risk factors for each patient with sepsis or septic shock and using empiric antibiotics that cover methicillin-resistant Staphylococcus aureus (MRSA), double-coverage for gram-negative pathogens, and coverage for fungal pathogens for patients who are at high risk for infection with these organisms. Regarding double coverage, factors that may be considered include confirmed infection or colonization with antibiotic-resistant organisms within the preceding year, local prevalence of antibiotic-resistant organisms, hospital-acquired/healthcare−associated infections, broad-spectrum antibiotic use within the preceding 90 days, concurrent use of selective digestive decontamination, travel to a highly endemic country, or hospitalization abroad within the preceding 90 days.
The guidelines provide several recommendations for optimizing antibiotic dosing, such as prolonged infusion of beta-lactams for maintenance (after an initial bolus) over conventional bolus infusion; addressing source control, such as with promptly removing intravascular access devices that can be a possible source of sepsis or septic shock after other vascular access has been established; and determining duration of antimicrobial therapy with daily consideration for de-escalation or discontinuing antibiotics.8 This is especially important if an alternative cause of illness is demonstrated or strongly suspected. Overall, it is most important that antimicrobial choice be tailored to each individual.
Hemodynamics
The guidelines suggest balanced crystalloids over normal saline.8 One of the studies to support this recommendation found that in a large randomized trial of patients with sepsis, the use of balanced crystalloids was associated with a lower 30-day in-hospital mortality compared with saline.17 A systematic review and meta-analysis showed the estimated effect of using balanced crystalloids vs. saline in critically ill adults ranges from a 9% relative reduction to a 1% relative increase in the risk of death, with a high probability that the average effect of using balanced crystalloids is to reduce mortality.18 For patients with septic shock, the guidelines recommend norepinephrine as the first-line vasopressor.19
A new recommendation advises that vasopressors be started peripherally to avoid delays in vasopressor administration in the absence of central venous access.8 Studies have supported this practice and found lower complication rates, faster time to shock resolution, and avoidance of central venous catheter placement altogether.20-22 Peripherally administered vasopressors should be given only for a short time period and in a vein that is in or proximal to the antecubital fossa. Guidelines for the safe peripheral infusion of vasopressors include a vein diameter > 4 mm as measured by ultrasound, the position of peripheral IV (PIV) access documented with ultrasound to be in the vein prior to starting the infusion, only upper extremity contralateral to the blood pressure cuff, IV line of 20 or 18 gauge, and use of proximal veins. The guidelines recommend blood return from PIV access prior to administration, assessment of PIV access function every two hours by nursing, and immediate alert by nursing staff to the medical team if line extravasation with prompt initiation of local treatment. Regardless of how careful the infusion of vasopressors is, the guidelines stress they should be administered only for a short period of time.
Unfortunately, the authors of the guidelines thought there was insufficient evidence to make a recommendation about the use of a restrictive vs. liberal fluid strategy after the initial fluid resuscitation.8,23-25 The literature on the amount of fluid to administer to patients after initial resuscitation in septic shock is evolving. Although current guidelines recommend a 30 mL/kg crystalloid bolus, this may not apply to patients who have been previously resuscitated. Randomized clinical trials, specifically the Crystalloid Liberal Or Vasopressor Early Resuscitation in Sepsis (CLOVERS) trial and the Conservative vs. Liberal Approach to Fluid Therapy of Septic Shock in Intensive Care (CLASSIC) trial, currently are underway and compare a liberal vs. restrictive approach to fluid resuscitation.26,27 After a scheduled interim analysis of the CLOVERS trial, an independent data and safety monitoring board found that the outcomes were similar in the two arms and that further enrollment was unlikely to change the result. Formal analyses of study data are ongoing, and findings are forthcoming. Similar to the 2016 guidelines, albumin is recommended in patients who have received considerable volumes of crystalloid, especially since there is evidence showing higher blood pressure at early and later time points.28
Ventilation
As for ventilation strategies, there was no formal recommendation regarding the use of liberal vs. conservative oxygen targets because of insufficient evidence. However, guidelines did support the use of high-flow nasal cannula (HFNC) over noninvasive mechanical ventilation because of improved 90-day survival in the HFNC group.8,29 The guidelines also recommend a ventilation strategy with low tidal volume with limitation of plateau pressure for patients with sepsis-associated acute respiratory distress syndrome (ARDS), with the addition of prone positioning in moderate-to-severe ARDS for greater than 12 hours a day.30,31 Rescue extracorporeal membrane oxygenation (ECMO) may be considered in selected patients with sepsis-induced severe ARDS in experienced centers.29
Additional Therapies
The updates for the 2021 guidelines specifically addressed vitamin C and IV corticosteroids.8 The 2021 guidelines suggest the use of IV corticosteroids for patients with an ongoing requirement for vasopressor therapy based on newer clinical trial data. This is now a weak, moderate-quality evidence, which is an upgrade from weak recommendation, low quality of evidence. Since the 2016 guidelines, several randomized controlled trials along with a meta-analysis revealed faster shock resolution and increased vasopressor-free days in patients treated with systemic steroids.32-34 The meta-analysis further cited benefits with regard to shock duration, duration of mechanical ventilation, and ICU length of stay, but also noted increased adverse events, including muscular weakness. The guidelines also recommend “against using IV vitamin C for sepsis or septic shock.” Although a before-and-after study published in 2017 found reduced mortality with vitamin C, thiamine, and hydrocortisone, the VITAMINS trial found no effect on mortality.35,36 Furthermore, a meta-analysis evaluating vitamin C also found no mortality benefit.37
Goals of Care and Long-Term Outcomes
The annual number of patients admitted to the ICU continues to grow, with most recent estimates reaching 5.7 million.38 Since there are increasing numbers of critically ill patients, sepsis survivorship also has grown as an important public health concern, with a significant number of survivors experiencing long-term morbidity and adverse health outcomes, including post-intensive care syndrome (PICS). PICS is defined as new or worsening physical, cognitive, or mental health status impairment arising after critical illness and persisting beyond acute care hospitalization.39,40 The 2017 World Health Organization resolution on sepsis pointed out “sequelae of sepsis can include clinically significant physical, cognitive, and psychological disability that often goes unrecognized and untreated” and called for improving outcomes of sepsis survivors and addressing survivors’ access to optimal follow-up care. Because of this burden, the guidelines now stress the importance of screening for economic and social support, including housing and nutritional, financial, and spiritual support, and making referrals to meet these needs.8 Guidelines also recommend offering and/or providing both written and verbal sepsis education prior to hospital discharge and in the follow-up setting, along with information regarding the diagnosis and common impairments after sepsis. If impairments are known, the recommendation is to set up patients with appropriate follow-up addressing the new and long-term sequelae prior to discharge. There also is a recommendation for assessment and follow-up for physical, cognitive, and emotional problems after discharge.
Summary
Updated global adult sepsis guidelines, released in October 2021 by the Surviving Sepsis Campaign, place an increased emphasis on improving the care of sepsis patients not only during hospital admission but also after ICU discharge. These guidelines continue to emphasize the importance of immediate bundle initiation ideally within the first hour. They continue to stress vital principles, such as early, appropriate antibiotics and fluid administration. Specifically, guidelines support a uniform first fluid bolus, specifically highlighting balanced crystalloid solutions for all patients. The administration of vasopressors may be initiated via peripheral access within a very limited time frame as opposed to waiting for placement of central venous access. Finally, follow-up for long-term physical, cognitive, and emotional sequelae frequently seen after critical illness was strongly emphasized.
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- Hernandez G, Ospina-Tascon GA, Damiani LP, et al. Effect of a resuscitation strategy targeting peripheral perfusion status vs serum lactate levels on 28-day mortality among patients with septic shock: The ANDROMEDA-SHOCK randomized clinical trial. JAMA 2019;321:654-664.
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- Fujii T, Luethi N, Young PJ, et al. Effect of vitamin C, hydrocortisone, and thiamine vs hydrocortisone alone on time alive and free of vasopressor support among patients with septic shock: The VITAMINS randomized clinical trial. JAMA 2020;323:423-431.
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Subsequent revisions of Surviving Sepsis guidelines highlighted the need for early, appropriate antibiotics along with a new focus on initial resuscitation, stressing the importance of dynamic measurements instead of static variables to predict fluid responsiveness. The most recent 2021 revisions continue to stress the importance of these ideals, but they also place an increased emphasis on the hour-1 bundle and improving the care of sepsis patients after they are discharged from the intensive care unit.
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