Sepsis and septic shock represent an enormous global burden, affecting millions of individuals each year.1,2 Similar to other medical emergencies, such as myocardial infarction, stroke, and trauma, a timely protocolized approach to the identification and management of sepsis and septic shock is believed to improve clinically important outcomes. This review explores the foundational studies and historical circumstances that ultimately culminate in the current sepsis bundles.
The Origin of Protocolized Therapy
Prompted by advances in basic science and clinical research, both the definition and the management of sepsis have evolved considerably in recent years. In 1991, the American College of Chest Physicians (ACCP) and the Society of Critical Care Medicine (SCCM) first put forth a uniform definition of sepsis and provided guidelines for management to improve early detection, standardize therapies, and facilitate further research.3 The CCP/SCCM Consensus Conference Committee distinguished between sepsis, a term specific to infection, and systemic inflammatory response syndrome (SIRS), which characterizes an inflammatory state arising from any noninfectious etiology, such as trauma, burns, and pancreatitis. SIRS was defined as ≥2 of the following criteria: (1) body temperature >38°F or <36°F; (2) heart rate >90 beats per minute; (3) tachypnea, manifested by a respiratory rate >20 breaths per minute, or hyperventilation, as indicated by a PaCO2 of <32 mm Hg; and (4) an alteration in the white blood cell count to >12,000 or <4000 cells per microliter, or the presence of >10% immature neutrophils (bands). Sepsis was defined as SIRS resulting from infection (suspected or confirmed).
In addition to simply defining sepsis, the Consensus Conference Committee also devised a grading system for capturing the severity of sepsis. “Severe sepsis” was defined as sepsis associated with organ dysfunction, hypoperfusion (eg, lactic acidosis, oliguria, altered mental status), or hypotension, in this case a systolic blood pressure (SBP) <90 mm Hg or a fall in SBP of ≥40 mm Hg relative to baseline, excluding other causes for hypotension (eg, cardiogenic shock). “Septic shock” was further defined as sepsis-induced hypotension that persisted despite adequate fluid resuscitation.
The 2001 landmark study by Rivers et al4 changed the early management of sepsis by showing a mortality benefit with the use of a rigorous protocol-based approach to sepsis treatment. Patients presenting with severe sepsis or septic shock (SBP of ≤90 mm Hg or lactate of ≥4 mmol/L after an initial 30 mL/kg crystalloid bolus) in the emergency department were assigned to receive an early goal-directed therapy (EGDT) protocol or standard of care. The 6-hour EGDT protocol included continuous monitoring of central venous pressure (CVP), central venous oxygen saturation (ScvO2), urine output, and mean arterial pressure (MAP). On the basis of these parameters, quantified therapies such as crystalloid fluids, vasopressors, red blood cells (RBC), and inotropes were administered in a protocolized manner. The authors reported a significant reduction in the primary outcome of in-hospital mortality (30.5% in the EGDT group versus 46.5% in the standard therapy group, P-value=0.009). After this study, many institutions began to implement EGDT for sepsis management.5
The Surviving Sepsis Campaign and the Introduction of Bundles
In 2002, SCCM and the European Society of Intensive Care Medicine (ESICM) created the “Surviving Sepsis Campaign” (SSC) and issued the “Barcelona Declaration” calling for worldwide action to diagnose and treat sepsis more effectively, with the stated goal to reduce mortality by 25% in 5 years. The SSC recommended the adoption of a single definition for sepsis, early diagnosis, and treatment with consistent clinical protocols, early referrals for treatment, education of clinicians, and counseling to provide quality post-intensive care unit (ICU) care. Over the next several years, the SSC Steering Committee met to develop international consensus guidelines, which included evidence-based recommendations on early fluid resuscitation, vasopressor use, antibiotic utilization, biomarker interpretation, and adjunctive therapies, among others.6 These guidelines borrowed heavily from the protocol established by Rivers and colleagues, in addition to emerging studies describing protocolized treatment.7–9
In response to emerging evidence highlighting the benefits of early intervention in sepsis, the SSC Steering Committee developed treatment bundles to standardize care in the management of patients with septic shock. The initial bundles devised by the Steering Committee spanned the first 6 and 24 hours of patients’ care.6 In 2012, the Committee revised their initial management strategy, abandoning the 24-hour bundle altogether and splitting the 6-hour bundle into 3- and 6-hour bundles.10 The 3-hour bundle recommended that within the first 3 hours of the recognition of sepsis, one should:
- measure lactate level;
- begin rapid administration of 30 mL/kg crystalloid for hypotension (ie, SBP <90 mm Hg or MAP <65 mm Hg) or lactate ≥4 mmol/L;
- obtain blood cultures before the administration of antibiotics; and
- administer broad-spectrum antibiotics.
The 6-hour bundle recommended:
- remeasurement of lactate if the initial value was >2 mmol/L; and
- initiation of vasopressors if hypotension persisted after fluid administration.
The bundles provided a much-needed timeframe for early intervention in sepsis and reflected the evolving approach to sepsis management that focused on prompt and aggressive algorithmic treatment.
Refinement of Protocolized Therapy
A reexamination and refinement of the accepted protocolized therapy occurred in 2013, but stemmed from much earlier criticisms of EGDT, despite adoption at many institutions and endorsement and integration into the SSC. Much of the criticism of the Rivers trial revolved around its resuscitation goals and methodology,11 including the use of CVP to determine intravascular volume status and ScvO2 as a surrogate for tissue oxygenation, both of which have been debated as adequate markers.12 EGDT also called for the administration of RBC to improve oxygenation, which has been contested.13 Additional criticisms include the fact that the study was carried out at a single center and treating clinicians were not blinded to group allocation. Moreover, the standard therapy group had a higher than average mortality rate, indicating a population with greater morbidity at baseline, calling into question the appropriateness of the standard-of-care group as representative of typical acuity.13,14 A closer look at the therapies administered in this study reveals relatively high rates of RBC administration and pulmonary artery catheterization in both groups, and excessive resuscitative fluid administration in the initial 72 hours of management (with the EGDT group receiving significantly more fluid in the first 6 h). In both groups, the mean duration of mechanical ventilation was 9 days despite a mean duration of vasopressor use of about 3 days, suggesting that the large amount of fluid and blood products administered to patients may have contributed toward the persistent need for respiratory support.
Three large international randomized controlled trials (RCT) were conducted and published between 2013 and 2015 in an effort to reevaluate the appropriateness of the EGDT algorithm.15–17 The 31-center, 1343-patient “Protocol-based Care for Early Septic Shock” (ProCESS) trial in the United States assessed all-cause 60-day in-hospital mortality of patients receiving 3 different sepsis treatment algorithms: EGDT, a protocol-based standard therapy, or the “usual care” delivered at each participating institution.13 Similarly, the 51-center, 1591-patient “Australasian Resuscitation in Sepsis Evaluation” (ARISE) trial directly compared EGDT with “usual care” to determine 90-day all-cause mortality.16 Finally, the 56-site, 1260-patient “Protocolised Management in Sepsis (PROMISE)” trial assessed 90-day all-cause mortality in patients receiving EGDT compared with “standard care,”17 In short, all 3 major studies failed to identify a mortality benefit for using EGDT versus usual care or an alternative resuscitative strategy. A subsequent 2015 meta-analysis of 11 RCTs, including EGDT, ProCESS, ARISE, and PROMISE, found no mortality benefit to EGDT in patients with septic shock who were treated with EGDT versus an alternate strategy.18 The study did, however, identify a significant increase in ICU admission rates when EGDT was implemented, suggesting ineffective resource utilization with this strategy. Similarly, a patient-level meta-analysis published in 2017 by the Protocolized Resuscitation in Sepsis Meta-Analysis (PRISM) Investigators, which included the ProCESS, ARISE, and PROMISE trial investigators, used pooled data from the 3 trials to compare outcomes between EGDT and “usual care.”19 The study found no mortality difference at 90 days, but the EGDT arm resulted in an increased use of vasopressors or inotropes, a higher rate of ICU admissions, and longer ICU stays. The PRISM authors argued that, because of the evolution in the standard-of-care recognition and treatment of septic shock, the lack of mortality difference might have stemmed from the general adoption of algorithmic treatment principles in septic shock.
Formalizing the Process
In 2015, the United States Centers for Medicare and Medicaid Services (CMS) mandated a documentation system for the management of severe sepsis and septic shock, whereby the SSC’s 3- and 6-hour treatment bundles became CMS “core measures” with which hospitals had to comply and report their compliance. This CMS core measure was termed “SEP-1” and, although it only required hospitals to report their compliance, the implication was that performance of the bundles would eventually be tied directly to billing and reimbursement.20
Supporting SEP-1 was an accumulating body of evidence indicating that compliance with the SSC bundles was associated with an improvement in patient-centered outcomes.21–25 Levy and colleagues published the results of a retrospective analysis of 29,470 patients examining compliance with SSC bundles over a 7.5-year period. Lower mortality was observed in sites with a higher rate of compliance (29.0%) versus ones with a lower rate of compliance (38.6%) (P<0.001).21 Similar results were found in a retrospective study of 182 patients in surgical ICUs in which survival was associated with adherence to an increasing number of therapeutic guidelines comprised of bundled care [odds ratio (OR), 1.64; 95% confidence interval, 1.28-2.1; P<0.001].22 A prospective multicenter cohort study in the Netherlands compared 8387 patients in 52 ICUs who were participating in sepsis bundle programs with 8031 patients in 30 nonparticipating ICUs, and found that participation in bundle programs decreased in-hospital mortality by 5.8% over 3.5 years.24 The 3- and 6-hour bundles were evaluated in the International Multicentre Prevalence Study on Sepsis (IMPreSS), which included 1794 patients from 62 countries and compared bundle compliance and mortality.23 Compliance with the 3-hour bundle was only 19%, but was associated with lower hospital mortality than noncompliance (20% vs. 31%, P<0.001). Similarly, compliance with all 6-hour bundle metrics was 36%, but was associated with lower hospital mortality than noncompliance (22% vs. 32%, P<0.001). Importantly, compliance with bundled therapy was associated independently with improvements in hospital mortality (3-h bundle OR: 0.64, P=0.004; 6-hour bundle OR: 0.71, P=0.005).
Refining the Definition of Sepsis
In 2016, a task force supported by SCCM and ESICM published the Third International Consensus Definitions for Sepsis and Septic Shock, or “Sepsis 3.0.”26 The group defined sepsis as life-threatening organ dysfunction caused by a dysregulated host response to infection. Septic shock was defined as a lactate level ≥2 mmol/L in the absence of hypovolemia, along with the need for vasopressors to maintain a MAP≥65 mm Hg. The task force used data obtained from 1.3 million electronic medical records from 12 hospitals in southwestern Pennsylvania to identify clinical parameters that correlated most accurately with sepsis-related patient outcomes. These findings were then validated using four data sets of >700,000 patients from 165 hospitals in the United States and Germany.27 The diagnosis of sepsis required suspected or documented infection and an acute change in the Sepsis-related Organ Failure Assessment (SOFA) of ≥2 points. The task force found that an increase in the SOFA score of ≥2 compared with the baseline correlated with a 10% risk of mortality in ICU patients with suspected infection.15 Moreover, outside of the ICU, they found that an abbreviated SOFA assessment called the “quick SOFA” or “qSOFA” similarly predicted mortality. Therefore, they recommended utilizing qSOFA, comprised of tachypnea (≥22 breaths per minute), altered mental status (Glasgow Coma Scale <15), and SBP≤100 mm Hg.27 By assigning one point for each abnormal finding, a score of ≥2 predicted greater mortality than the presence of any single criterion. In addition to its ease of use, this definition had the advantage of being derived and validated from observational data.
Nonetheless, a great deal of controversy surrounds the Sepsis 3.0 definition.28 For example, the previous sepsis definition utilizing the highly sensitive SIRS criteria as the screening tool to help identify patients with sepsis suffered from poor specificity, which led to high resource utilization in a cohort of patients who uniformly did well without aggressive resuscitative efforts.29 Sepsis 3.0 is considered to be more consistent with the underlying physiology of sepsis,26 but is not as sensitive as the SIRS criteria.
In one prospective analysis comparing SIRS and qSOFA screenings tools, Freund et al30 reported an 8% overall mortality in a cohort of patients admitted from the ED with suspected infection. The in-hospital mortality was 3% in patients with a qSOFA score <2 compared with 24% in-hospital mortality in those with a qSOFA of ≥2. Similar to patients with a qSOFA<2, in-hospital mortality for patients with <2 SIRS criteria was 2.2%. However, unlike a qSOFA ≥2, two or more SIRS criteria did not identify a group of patients with a higher in-hospital mortality than that of the entire cohort (10.6% vs. 8%). This suggests that, although SIRS criteria can identify a cohort at very low risk for in-hospital death, it cannot identify those septic patients at high risk for death. A recent analysis of eight cohorts in low-income and middle-income countries by Rudd et al31 and a meta-analysis of the various studies comparing SIRS with qSOFA both found similar results.32
Assimilation of the SSC, the Bundles, and Sepsis 3.0
The SSC guidelines were subjected to multiple radical changes in the 2016 update,33 published after PROMISE, ProCESS, and ARISE failed to find a mortality benefit specifically through the use of EGDT. The updated guidelines reflected these findings, deemphasizing the need for invasive monitoring strategies, such as measuring CVP or ScvO2, opting rather for simpler and less invasive methods of monitoring a patient’s response to initial resuscitative efforts. In addition, compared with the 2012 guidelines, which defined sepsis as infection-induced SIRS, the 2016 addition incorporated the Sepsis 3.0 definition.26 Consistent with the Sepsis 3.0 definition, the category of severe sepsis (previously defined as sepsis with signs of organ dysfunction) was removed from the guidelines. Currently, the SSC guidelines divide sepsis into two categories: sepsis (suspected infection with organ dysfunction) and septic shock (sepsis with hypotension and a lactate >2 after initial resuscitative efforts). Although the SSC embraces the Sepsis 3.0 definition, it also notes that many institutions have established sepsis treatment protocols on the basis of the former SIRS-based definition and therefore recommends that these institutions not be required to change their protocols.
Introduction of the 2018 1-Hour Bundle
The 2016 update of the SSC guidelines refers extensively to the 3- and 6-hour therapeutic bundles, endorsing the achievement of diagnostic and treatment goals within a specific timeframe. In 2018, the SSC bundles were subjected to a major revision, in which the 3- and 6-hour bundles were eliminated in favor of a 1-hour bundle34 (Fig. 1). Central to this revision is the widely accepted belief that sepsis is a medical emergency and that immediate management is associated with improved outcomes.9,35,36 This bundle requires the initiation of the following elements within 1 hour of ED triage or, if referred from another care location, from the earliest chart annotation consistent with all elements of sepsis (formerly severe sepsis) or septic shock, as ascertained through chart review:
- measure lactate level; remeasure if initial lactate is >2 mmol/L;
- obtain blood cultures before the administration of antibiotics;
- administer broad-spectrum antibiotics;
- begin rapid administration of 30 mL/kg crystalloid for hypotension or lactate ≥4 mmol/L; and
- apply vasopressors if the patient is hypotensive during or after fluid resuscitation to maintain MAP ≥65 mm Hg.
Despite the extensive literature review by Levy et al,34 the evidence supporting the 1-hour bundle is far from robust. The following is a review of each recommendation, along with the strength of the evidence supporting its use.
The 1-hour bundle recommends that the initial lactate be drawn within 1 hour of presentation, and, if elevated, should be remeasured within 2 to 4 hours. This recommendation stems from various RCTs showing improved outcomes when lactate-guided resuscitation strategies are utilized.37–39 Importantly, although all 3 of the trials used to support the 1-hour bundle recommendation examined the use of lactate as part of a resuscitation strategy, only one of these trials actually identified a statistically significant survival benefit in patients randomized to a lactate-guided resuscitation strategy.39 The 2 larger statistically robust trials found no survival advantage in patients randomized to a lactate-guided resuscitation strategy and one found that such a strategy was associated with greater fluid administration over the initial 8 hours of care.37 Since the publication of these trials, the understanding of lactate generation in sepsis has evolved. A substantial portion of the increase in serum lactate levels observed in patients with sepsis does not directly result from tissue hypoxia, but rather reflects an increase in sympathetic tone as a direct response to infection.40,41 Nonetheless, lactate remains a good prognostic marker of a patient’s severity of illness and is valuable in the initial workup of a patient with sepsis.42,43 Because lactate production is not specific to sepsis and elevations can be observed due to a multitude of acute stressors,44 early increases in serum lactate may not necessarily be because of tissue hypoxia; clinicians should administer additional fluid with caution. Persistent elevations in serum lactate should prompt further investigation into a patient’s cardiac function, determination of whether adequate source control has been achieved, and identification of other potential sources of lactate generation (eg, high-dose epinephrine infusions, mitochondrial toxins, cofactor deficiencies).
Blood Cultures Before Antibiotics
The current 1-hour bundle encourages obtaining blood cultures before the administration of broad-spectrum antibiotics, but they caution not to delay antibiotic administration at the expense of collecting cultures. Although some low-quality data suggest that sterilization of blood occurs as early as 30 minutes after the administration of broad-spectrum antibiotics, the yield of positive blood cultures acquired even before the administration of antibiotics varies widely (14.5% to 60.6%) in patients with sepsis.45,46 More importantly, the occasions when these blood cultures change clinical care is infrequent. Given that no studies have ever found improvement in patient-centered outcomes associated with obtaining blood cultures in patients with sepsis, delay in the administration of antibiotics to obtain blood cultures is not advised.
The 1-hour bundle recommends the administration of broad-spectrum antibiotics to be initiated within 1 hour of identification of patients with suspected sepsis. This recommendation is based on multiple studies suggesting a temporal benefit to early, appropriate antibiotics in patients presenting with sepsis or septic shock.25,35,36,47 Despite strong physiological plausibility supporting timely antibiotics, the actual evidence supporting earlier administration is ambiguous. The data cited by the authors supporting earlier administration of antibiotics originate from observational cohorts that show an association between earlier antibiotic administration and decreased mortality. Without randomization, however, numerous confounders may bias these observed results. Even in these observational cohorts, the temporal benefit of antibiotic administration was only observed in sicker subsets of septic patients. The only RCT cited by the 1-hour bundle author, which examined early antibiotic administration in patients with suspected sepsis in the prehospital setting, showed equivocal results. Despite receiving antibiotics ∼90 minutes earlier than the comparator, patients administered early broad-spectrum antibiotics (in an ambulance by paramedics) fared no better than those randomized to the traditional administration in the ED.48
Fluid Bolus of 30 mL/kg
The fluid bolus recommendation may be the most controversial in the current 1-hour sepsis bundle. The 1-hour bundle recommends that initial fluid resuscitation begin immediately upon recognizing sepsis and/or hypotension and elevated lactate, and should be completed within 3 hours. Unchanged from previous bundle recommendations is the required minimum administration of 30 mL/kg intravenous crystalloid fluid. Although this fluid volume is consistent with standard of care, a growing body of literature documents the harms of excess fluid administration.49–51 In fact, one trial cited by the authors of the 1-hour bundle could not show any temporal benefit to early fluid resuscitation.35 Two RCTs, the REFRESH and CLOVERS trials, are currently attempting to determine the optimal fluid resuscitation strategy in patients with sepsis and septic shock.52,53 A prudent approach tailored to the individual patient, keeping in mind preinfectious fluid status and objective findings of fluid responsiveness (with bedside ultrasound, for example), may be the best course of action.
Apply Vasopressors for a MAP ≥65 mm Hg
The recommendation on the management of vasopressor therapy represents the most important change in the 2018 version of the SSC bundle. Historically, the recommendations encouraged adequate fluid resuscitation before initiating vasopressor agents. The 1-hour bundle recommends early use of vasopressors, in parallel with fluid resuscitation, to provide an adequate perfusion pressure to the vital organs. Multiple observational and retrospective analyses have examined whether early vasopressor initiation affects patient outcomes. A retrospective study in surgical ICU patients with septic shock found a significant difference in 28-day mortality between the early (29.1%) and late initiation of norepinephrine (43.3%).54 A regression analysis showed a risk of death with each hour of delay of norepinephrine administration, with OR 1.20 (1.07-1.37, P=0.002). However, additional studies found only small statistical associations of questionable clinical relevance or failed to identify any effect of early initiation of vasopressors.55,56 Although the recommendation of early aggressive use of vasopressors to maintain a MAP of ≥65 mm Hg is supported by plausible physiological reasoning, these discordant empiric results highlight the importance of RCTs to derive a clear effect of vasopressor timing on mortality and other outcomes of interest.
In addition to timing of vasopressors, little is known about the ideal MAP target in patients with septic shock. The current SSC guidelines and 1-hour bundle recommend a minimum MAP of ≥65 mm Hg. Despite this recommendation, no robust data support a single MAP goal for all patients presenting with septic shock. In fact, many small trials have shown improvements in microcirculation and end-organ oxygen saturation when MAP goals well above 65 mm Hg were utilized.57 To date, only one multicenter RCT has examined MAP goals in patients with septic shock.58 At 28 and 90 days, the authors found no significant differences in mortality in the high-MAP and low-MAP groups. A lower need for renal replacement therapy in patients with chronic hypertension was observed in the high-MAP group; however, this was contrasted with a higher incidence of atrial fibrillation. These hypothesis-generating results suggest that an individualized approach that considers optimizing end-organ perfusion, not a singular MAP goal, may be preferred.
Deficiencies With the 1-Hour Bundle
A prudent criticism of the 1-hour bundle is appropriate, given the emphasis afforded to its predecessors (ie, 3- and 6-h bundles) by CMS, quality agencies, and health care entities worldwide. The majority of the evidence used to support the introduction of the revised 1-hour bundle comes from observational data35 and shows association, but not necessarily causation.59 Importantly, the temporal decrease in overall sepsis mortality is not evidence that the SSC treatment bundles are beneficial; similar mortality reductions have occurred in Australia and New Zealand, countries that have not endorsed the SSC treatment bundles.60 Furthermore, evidence supporting the 1-hour bundle is largely from observational studies21–25,35 that examined earlier versions of the SSC bundles. None of this evidence explicitly studied the benefits of a 1-hour treatment bundle. In fact, many RCTs have called into question the individual components of protocolized therapies used in these observational analyses.15–17
A great deal of progress has been made in the understanding of the underlying physiology and treatment strategies of sepsis and septic shock. Much has changed since the earliest iterations of guidelines from the SSC. A protocolized approach to the treatment of sepsis and septic shock has been proven to be beneficial, and although the exact protocol continues to evolve, a few key elements have persisted, including early identification and source control, fluid resuscitation, blood pressure support, and objective timely reevaluation. Timely treatment and evaluation, as emphasized in the SSC bundles, have underscored the belief that sepsis and septic shock are medical emergencies. However, both the SSC guidelines and the bundles must be interpreted and executed with caution because much of the evidence is circumstantial and may be associated with unintended consequences. The proposed 1-hour bundle, for example, may restrict the time allotted to providers for the identification and treatment of patients with suspected sepsis, and adherence to this mandate may result in the needless exposure to aggressive resuscitative measures with modest evidence of benefit. However, the evolution in sepsis recognition and treatment has clearly led to improved patient outcomes, and future efforts and research should be met with cautious optimism.
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