Despite decades of progress, sepsis remains a major cause of death and disability (1). Recognizing the high burden of sepsis, the Centers for Medicare and Medicaid Services (CMS) implemented the Severe Sepsis and Septic Shock Early Management Bundle (SEP-1) in 2015. This measure generated strong reactions from many clinicians, administrators, and policymakers.
SEP-1 brought welcome attention to sepsis, created more accountability for sepsis care, and catalyzed numerous quality improvement initiatives. At the same time, there is growing concern that there may be unintended consequences of sepsis mandates and the culture of “treat first, ask questions later” that they encourage.
Critics of SEP-1 recall the well-intended but ill-fated CMS community-acquired pneumonia measure requiring clinicians to give antibiotics to patients within 4 hours of hospital arrival. This measure led to an increase in inappropriate antibiotic prescribing but no appreciable decrease in mortality (2). Over the past several years, we have seen a similar effect at sites seeking to comply with the antibiotic time threshold in SEP-1; this is magnified by the Surviving Sepsis Campaign’s recent recommendation to target even shorter goals (3). Setting aggressive time-to-antibiotic targets for all patients with sepsis risks causing more harm than time-to-antibiotic targets for pneumonia because sepsis is even more complicated and prone to misdiagnosis than pneumonia. Clinicians are faced with the challenge of differentiating infected patients from uninfected patients despite the fact that their presentations are often similar. Pressure to administer antibiotics quickly risks forcing premature diagnostic closure, overclassification of patients as infected, and ultimately administration of antibiotics to patients who will not benefit from them and may be harmed by them. Importantly, up to 40% of patients initially treated for sepsis turn out to have a low likelihood of infection when assessed retrospectively (4).
Antibiotic stewardship, also a national priority, demands a better approach. A Centers for Disease Control and Prevention recent report estimates 35,000 death per year in the United States due to antibiotic resistance and another 12,800 from Clostridium difficile (5). Even short courses of antibiotics can increase antibiotic resistance, acute kidney injury, C. difficile infection, and disruption of the gut microbiome (6–8). How and where do we draw the regulatory line between which patients should receive immediate broad-spectrum antibiotics per SEP-1 and which are better served by taking a small amount of time to gather more evidence for or against infection before treating?
The Infectious Diseases Society of America (IDSA), with the endorsement of the American College of Emergency Physicians, Society for Healthcare Epidemiology of America, Pediatric Infectious Diseases Society, Society for Infectious Disease Pharmacists, and Society of Hospital Medicine will offer recommendations to improve the utility and safety of SEP-1 (C. Rhee, unpublished observations, 2020). As authors and endorsers of that position paper who are also actively involved in critical care medicine and emergency care, we advocate for changes to reduce the risk of unintended consequences of the bundle while maintaining a strong focus on its evidence-based elements. Our focus here is on issues related to the diagnosis and management of infection, although we also believe that other aspects of SEP-1, particularly those related to fluid administration and patient reassessment, would also benefit from a similar reconsideration.
Our core recommendation is to focus antibiotic timing thresholds on septic shock patients alone, moving away from the current approach which targets strict timing thresholds for all patients with any forms of possible sepsis (and often something else instead). We summarize the reasons for this below.
WHY SEP-1 SHOULD FOCUS ON SEPTIC SHOCK AND NOT SEVERE SEPSIS
Focusing SEP-1’s Antibiotic Timing Requirement on Patients With Septic Shock Aligns the Measure With the Best Available Evidence
The perception that every patient with suspected sepsis requires immediate antibiotics to prevent poor outcomes, regardless of their severity of illness or likelihood of true infection, contributes to antibiotic overprescribing. This mindset ignores the varying levels of certainty of infection, heterogeneous signs, infection sites, and severities of organ dysfunction encompassed by the term “sepsis.” (9) For example, does a patient with isolated hyperbilirubinemia or a minimally elevated lactate level need to be treated with the same urgency as a patient with persistent hypotension?
The primary studies cited by the 2016 Surviving Sepsis Campaign guidelines to support their recommendations on immediate antibiotics focused on critically ill patients, most of whom had septic shock (10–13). Two more recent studies included much larger numbers of sepsis patients with and without shock, reporting harm with hourly delays in antibiotics for all patients, but much smaller effects for sepsis without shock (14,15).
Other recent studies looking at time-to-antibiotics in sepsis patients without shock linearize the association between time-to-antibiotics and death over large time intervals (up to 24 hr or more in some cases) to yield statistically significant hourly effects even when mortality rates only significantly rise after about 5 hours (16,17). Furthermore, all observational studies are at risk for residual confounding. The only randomized trial to date comparing differential timing of antibiotics for sepsis found no difference in mortality rates despite greater than 90 minutes difference between study arms in time-to-antibiotics (18). Fewer than 4% of the patients enrolled in this study had septic shock; hence, the findings of this study are most pertinent to sepsis without shock.
The differential importance of time-to-antibiotics by level of illness has important implications for the initial workup of patients with possible sepsis. Patients who may have septic shock have less margin for error and are often easier to identify than patients without shock. Drawing blood cultures and starting broad-spectrum antibiotics immediately is wise in those with shock which appears possibly due to infection, even if the latter is uncertain while further evidence supporting or refuting the diagnosis of septic shock is gathered. Indeed, we recommend administering antibiotics to patients with possible septic shock within 1 hour given that this is a true medical emergency. For patients without shock, however, we suggest a more nuanced approach calibrated to the probability of infection and severity of illness. Patients with clear infections should be treated immediately. If the diagnosis of infection is unclear, however, we suggest rapid investigations to try to gain more diagnostic clarity before treating.
Using our suggested approach, we can lessen the rush to quickly give broad antibiotic coverage to many patients (absent shock) in whom there may have been concern for infection at time of first provider contact but do not in fact have an infection. We believe this lessens harm to individual patients without losing recovery opportunities, and this will aid antibiotic stewardship and help optimize antibiotic use for others. The clinical data needed to make the best infection and sepsis judgment can often be collected over a few hours, allowing one to determine if antibiotics are needed or if an appropriate regimen can be narrow rather than broad.
The Benefit of Bundled Care in Sepsis Without Shock Is Likely Overestimated by Observational Studies Due to Their High Risk of Bias
Proponents of sepsis mandates point to numerous studies demonstrating the beneficial impact of bundled care in patients with both sepsis and septic shock. These generally come in two types as follows: 1) before-after studies showing lower mortality rates after implementing sepsis bundles and 2) concurrent implementation studies that demonstrate associations between higher bundle compliance and lower sepsis mortality. Both of these types of studies are susceptible to bias.
“Before-after” studies generally include educational initiatives and enhanced screening protocols with sepsis bundle roll-outs. By design, this leads to increased detection of patients with earlier and milder forms of sepsis. In turn, this leads to an increase in the overall number of sepsis cases and a parallel decrease in mortality. The risk of ascertainment bias is magnified with administrative data such as International Classification of Diseases codes since coding for sepsis and organ dysfunction is becoming more complete over time (19,20).
In concurrent bundle implementation studies, there are several reasons why higher bundle compliance might be associated with lower mortality. One possibility, of course, is a causal relationship. Even then, though, the clearest links between bundle use and improved outcomes are in patients with septic shock (14). Second, bundle compliance might be a marker for better hospital care overall. Third, important confounders are not fully accounted for in observational data and create or magnify associations. For example, many patients fail to receive the mandated 30 cc/kg volume of fluids due to fear of fluid overload in patients with cardiac, respiratory, or renal dysfunction—all of which are important independent risk factors for mortality (21). Patients may have delays in receiving antibiotics because of other acute illnesses, difficulty in obtaining IV access (which tends to occur in older, sicker patients), or because patients’ presenting symptoms do not obviously point to infection. This last point is especially important as emerging data indicate that septic patients with vague presentations tend to be older, sicker, and have a higher risk of death (22).
Focusing SEP-1 on Septic Shock Would Simplify Abstraction of “Time Zero” and Make It a More Reliable Quality Metric
All of the time-sensitive actions currently required by SEP-1 are anchored against a complex “time zero” definition for severe sepsis. Time zero is defined as the first moment that all three of the following are present within a 6-hour window: 1) documentation of suspected infection, 2) greater than or equal to 2 systemic inflammatory response syndrome criteria, and 3) greater than or equal to 1 of many different organ dysfunction criteria. Abstractors searching for time zero need to sort through multiple progress notes, vital sign flow sheets, and laboratory results, a process that can sometimes take an hour or more per case.
The complicated organ dysfunction criteria are problematic since abstractors must often exercise considerable judgment in deciding whether organ dysfunction is new and whether it is attributable to infection. Not surprisingly, different abstractors often identify different time zeros, yielding very different interpretations of SEP-1 compliance (23). Adjudication and retraining by expert abstractors can improve reliability but is not always feasible or consistently performed across healthcare systems. Focusing on septic shock would simplify time zero identification and increase measure reliability.
GUIDANCE ON MANAGING SEPSIS WITHOUT SHOCK
Our recommendation to focus SEP-1 on septic shock is not meant to trivialize the importance of sepsis without shock. However, it is important to distinguish interventions required by regulatory measures versus those recommended in clinical practice guidelines. Regulatory measures are inherently less flexible than clinical guidelines and should be based on the highest quality of evidence. Regulatory measures are best when they are limited to clearly beneficial interventions and when they are attentive to potential unintended consequences.
Clinical guidelines, on the other hand, have more room for nuance since they are voluntary and provide graded recommendations with a summation of the supporting literature, possible gaps, and the rationale underlying the ultimate recommendation. As such, guidelines are the more appropriate forum for delivering direction on managing sepsis without shock. Hospitals may choose to go above and beyond what is required by regulatory measures and incorporate interventions recommended by clinical guidelines into their protocols, but these decisions should be up to the discretion of each hospital in accordance with their assessment of local needs and opportunities.
OTHER POTENTIAL WAYS TO IMPROVE ON SEP-1
We offer three additional suggestions that go beyond the ideas discussed in the IDSA position paper but that we believe could further enhance SEP-1’s benefits while strengthening CMS’s commitment to antibiotic stewardship.
SEP-1 Should Require Hospitals to Measure the Time From Antibiotic Order to Infusion for Patients With Septic Shock
Requiring hospitals to report the interval from when a clinician places a “stat” antibiotic order and the commencement of the infusion could help bring attention to the need to improve antibiotic delivery systems. This is important since emerging data suggest delays from antibiotic order to infusion are common and associated with mortality (24). Minimizing this time interval is a process issue that all healthcare facilities can work to improve.
If CMS chooses to retain sepsis without shock in the measure, focusing on this metric for all sepsis patients is a logical way to mitigate the current ambiguities around identifying time zero and maintain attention to delivering timely care in the entire spectrum of patients with sepsis while avoiding unnecessary pressure to start antibiotics in patients in whom clinicians believe infection to be unlikely.
SEP-1 Should Include a Requirement for Antibiotic “Time-Outs” for Clinicians, in Conjunction With Hospitals’ Antimicrobial Stewardship Teams, to Assess the Potential for Antibiotic De-Escalation or Cessation in Patients With Suspected Sepsis
We acknowledge the reality that clinicians, even in the absence of regulatory measures, will often continue to administer empiric broad-spectrum antibiotics in patients with suspected sepsis (even without shock). Mandatory and structured reassessments of antibiotic choice, spectrum, and necessity documented in the electronic medical record could mitigate the consequences of overly zealous treatment for possible sepsis, particularly if done collaboratively with antibiotic stewardship teams (25).
SEP-1 Reporting Should Be Feasible Using Automated Analyses of Structured Electronic Health Record Data
Due to SEP-1’s complexity, CMS currently requires hospitals to abstract and report a maximum of 60 sepsis cases per quarter. Patients transferred from other institutions, placed on comfort measures, or who do not meet the SEP-1 time zero criteria are subtracted from the list of patients to be reviewed so in practice many hospitals only report on a handful of patients each month. This means that large hospitals must extrapolate the quality of their sepsis care from a tiny fraction of their septic patients.
Now that electronic health record systems are almost universally used around the nation, SEP-1 should evolve into a completely automatable measure using a time zero definition that is readily extractible electronically. This will enable hospitals to monitor sepsis care across their entire population in a rapid, efficient, and objective fashion that can eliminate the need for onerous and subjective manual reviews.
We commend CMS and the stewards of SEP-1 for elevating sepsis to a national priority. The current SEP-1 bundle, however, encourages an institutional “rush to treatment” that may benefit some patients but may be potentially harmful in other patients. A more streamlined bundle focused on septic shock alone would help mitigate this risk by focusing the measure on the population most likely to benefit from immediate broad-spectrum antibiotics. This would also increase the efficiency and reliability of the current or any new sepsis measure.
We believe that professional societies with expertise in managing patients with sepsis in emergency departments, inpatient services, and ICUs should have a central role in developing, testing, and assessing future sepsis quality measures. We hope CMS will engage representatives from a wide array of professional societies to collaborate on refining SEP-1 to better encourage early effective care for the patients with sepsis who truly stand to benefit while also promoting a smarter and more rational approach to antibiotic use in everyone else.
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