October 17, 2017
9 min read

‘Sepsis’ is in the eye of the beholder

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The term “sepsis” has been surrounded by ambiguity and controversy. The condition has instigated legislative policies (eg, “Rory’s Regulations” — a New York state-mandated protocol for ED treatment of sepsis in hospitals), created CMS core quality measures with financial consequences and has been associated with fear and uncertainty on the part of both patients and medical providers. Almost certainly, we have all heard a patient or family member voice their joyful relief that they “don’t have sepsis, but only pneumonia,” unknowing that the medical field uses these two terms interchangeably in some cases.

Larry M. Bush
Donald Kaye

Whether developing guidelines for clinical practice or designing investigative research trials, we rely upon specific definitions for the entities we are treating or studying. However, long before the concept of “evidence-based medicine” became vogue, terms that may not have been well-understood or widely agreed upon often fashioned how we then practiced and in some ways still do. Even to this day, the assignment of a patient’s condition as either stable, guarded or critical seems to be more perceptually derived than measurably determined. Still, without question, be it infectious disease related or otherwise, the ability to better recognize a potentially serious condition early on in its course allows for prompt intervention with the proven benefits of reduced morbidity, mortality, length of hospital stay and overall expenditures. “Sepsis” is one such condition, because it is a significant but often unrecognized cause of illness both inside and outside the United States. Presently, sepsis accounts for one-third of in-hospital deaths (more than myocardial infarctions and cerebrovascular accidents), leads to the longest length of hospital stay and is the most expensive inpatient treated condition, making up 5.2% of hospital costs (approximately $20 billion) annually. In addition, the incidence of sepsis (either true or perceived) is reported to be increasing on an annual basis. Factors believed to contribute to the increase in numbers of cases include an aging population, more persons with immunosuppressive conditions or those receiving immune-modulating medications and more frequent invasive diagnostic and treatment procedures.

A landmark study by Rivers and colleagues, published in The New England Journal of Medicine in 2001, is most often cited as the first firm evidence-based proof that early recognition, along with what they termed early goal-directed therapy (EGDT), significantly reduced mortality from 46.5% to 30.5% in septic patients. Subsequent randomized controlled international trials (ProCESS, ARISE and ProMISe) comparing EGDT with “usual care” have failed to reproduce those same results. Nevertheless, a group of 55 international experts known as the “Surviving Sepsis Guideline panel” created 3- and 6-hour bundles that incorporate the early administration of IV crystalloid fluids and antibiotics, designed to reduce the number of avoidable deaths. In a publication entitled, “Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016,” they outlined in detail several steps to be employed in the early management of sepsis, which has been endorsed by CMS.

A working definition

Unfortunately, the problem has been, and perhaps remains, the lack of a clear consensus on what actually defines sepsis. Dating back to the 1980s and earlier, the concept of sepsis revolved around the systemic release of endotoxins from culprit microorganisms — a measurement still not clinically available. For others, the term “septicemia,” implying bloodstream infection, was the determining factor for when sepsis was present, even though most serious infections occur without bacteremia. In many instances, there is only a localized infection (ie, cellulitis, subcutaneous abscess).

To that end, the Society of Critical Care Medicine, together with the European Society of Intensive Care Medicine, convened a task force of 19 specialists from the fields of critical care, infectious diseases, pulmonology and surgery to develop a definition of sepsis. “The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3),” published in 2016, states that the new definition is based on our current understanding of sepsis-induced changes in organ function, morphology, cell biology, biochemistry, immunology and circulation — all referred to as pathobiology. This has resulted in a major shift in the delineation of sepsis, which, for 25 years — beginning with the first consensus conference in 1991 and expanded upon during a second sepsis conference in 2001 — was based strictly on clinical criteria known as the systemic inflammatory response syndrome (SIRS). This is a significant paradigm shift because the definition is now used to describe what sepsis actually is rather than using signs and symptoms.

Their main goal was to assist clinicians in differentiating sepsis from uncomplicated infection, because the former carries with it significant mortality that can be effectively reduced if recognized and treated early. To the credit of the group, they recognized that there is no one standardized test or criterion that would validate that a patient is truly septic but rather acknowledged that sepsis is a syndrome. The group arrived at their final Sepsis-3 definitions and clinical criteria after a retrospective analysis of electronic health record databases that included 1.3 million encounters at 12 community and academic hospitals, of which 148,907 patients were suspected to have infection. The suspicion of infection was identified as patients who had body fluids sampled for culture and received antimicrobial therapy. However, historically, culture-positive “sepsis” is observed in only 30% to 40% of cases. Those of us engaged in the clinical practice of infectious diseases are well aware of the superfluous ordering of unwarranted microbiologic tests and prescription of antibiotics that, according to the CDC, are either unnecessary or inappropriate in up to 50% of patients, many of which take place in the hospital setting. As stated in the Sepsis-3 document, the sepsis illness concept is predicated on infection as its trigger. Although the document acknowledges the pitfalls and challenges in the microbiologic identification of infection, it points out that it was not within the role of the task force to examine or stipulate the definition of infection; and therein lies the problem.


Furthermore, the task force unanimously considered that the up-until-now use of two or more SIRS criteria (pulse > 90 beats/min; respiratory rate > 20 breaths/min; leukocyte count > 12,000 cells/mm3, < 4,000 cells/mm3 or > 10% band forms; and temperature > 100.4 F° or < 96.8 F°) to be unhelpful. For years, those who have been critical of the use of SIRS in patients suspected or proven to have infection as the criteria for defining sepsis have focused their criticism on the overly sensitive nature of the parameters (ie, these parameters also occur with trauma, burns, surgery, etc.), which come at the expense of specificity. Furthermore, in at least 50% of individuals who qualify as having SIRS, this response is adaptive and appropriate for a localized infection and does not necessarily imply sepsis or an increased risk for dying. On the other hand, one recent study conducted in Australia and New Zealand looked at 13 years of patients with infection and organ failure and concluded that the need for two or more SIRS criteria to define severe sepsis excluded one in eight otherwise similar patients with infection, organ failure and substantial mortality, and failed to define a transition point in the risk for death. Nonetheless, since the incorporation of the SIRS criteria in the definition of sepsis, severe sepsis and septic shock, the mortality rate from these conditions has consistently declined, perhaps because of the inclusion of patients who are not septic to begin with, thus expanding the denominator.

SOFA score

Sepsis-3 now defines sepsis as “life-threatening organ dysfunction caused by a dysregulated host response to infection” — suspected or proven — based on the knowledge that when this occurs, patients have prolonged stays in the ICU and a significant risk for dying in the hospital with a mortality rate of 10%. Because sepsis poses a greater risk for in-hospital death than most other severe medical conditions, the previously used term, “severe sepsis,” which is defined as sepsis and organ dysfunction, has been abandoned because all sepsis is potentially severe. Septic shock is now considered a subset of sepsis, in which underlying circulatory and cellular/metabolic abnormalities are profound enough to substantially increase mortality (currently 42%). In other words, patients have “bad sepsis.” The clinical criteria for both entities are more relevant to practice. A sequential (sepsis-related) organ failure assessment (SOFA) score has been developed to include six parameters (see Table).

At least two of these parameters are used to define sepsis. This measure has been validated for use only in ICU patients. The assumption is that patients start with a SOFA score of 0, unless they have baseline abnormalities in the above-mentioned parameters, in which case an increase of two or more is required. Alternatively, a quick SOFA (qSOFA) score has been created and designed to be a clinically useful tool for ED and general floor patients to help identify those likely to have sepsis. Using the acronym HAT for hypotension (systolic blood pressure < 100 mm Hg), altered mental status (Glasgow Coma Scale score < 15), and tachypnea (respiratory rate > 22 breaths/min), the presence of at least two of these parameters serve as qualifiers and eliminate the need for laboratory data. The committee goes on to point out that it is important not to wait for a qSOFA score of at least 2 in order to initiate treatment in patients suspected of having infection. The newly proposed Sepsis-3 clinical criteria used to diagnose septic shock include having sepsis together with the need for vasopressor medications to maintain a mean arterial pressure, or MAP, greater than 65 mm Hg, despite adequate fluid resuscitation as well as a serum lactate level of more than 2 mmol/L. Not unexpectedly, even though 31 national and international societies have lent their support to Sepsis-3, some prestigious medical groups (eg, American College of Emergency Physicians and the Infectious Diseases Society of America) have not yet fully provided their endorsement. One major criticism of Sepsis-3 relates to a statement in the document, specifically: “sepsis-induced organ dysfunction may be occult; therefore, its presence should be considered in any patient presenting with infection. Conversely, unrecognized infection may be the cause of new-onset organ dysfunction. Any unexplained organ dysfunction should thus raise the possibility of underlying infection.” The fear is this may be too sensitive of a concept and lead to further unwarranted antibiotic use. Another criticism focuses on the very subjective concept of a dysregulated host response because, as stated by the authors of Sepsis-3, there are no current clinical measures to say when a response goes from regulated and helpful to dysregulated and harmful. And lastly, the suggestion by the panel that “health care practitioners require improved clinical prompts” to help with earlier identification of sepsis has in part led to the addition of a “code sepsis” alert when someone (often a nurse) checks off boxes, leading to frequent automatic telephone orders for unnecessary treatment and tests that otherwise would not be done if the patient underwent an adequate clinical evaluation.

To date, the new Sepsis-3 consensus definitions and guidelines have not resulted in any changes in the definition or treatment of sepsis on the part of hospital quality improvement departments or regulatory agencies, and sepsis is defined differently by Sepsis-3, CMS and the CDC. Likewise, the most recent Surviving Sepsis Campaign (SSC) guidelines still advocate the measurement of lactate as a key component of its 3-hour bundle, even though this laboratory measure is not a component of the SOFA or qSOFA clinical criteria now used to recognize and define sepsis. Along with rapid infection source control, these new SSC guidelines advocate for the administration of broad-spectrum antibiotics (after collecting blood cultures) as soon as possible and within a maximum of 1 hour. Although studies have demonstrated that delays in the delivery of antibiotics are associated with an increased risk for death, and that timely treatment is the single most important intervention clearly proven to affect mortality, the unanswered question remains: When does the clock actually begin in any one patient? Moreover, even though the use of empirical combinations of antibiotics received only a weak recommendation for therapy in patients with septic shock (but not in sepsis without shock), we can all attest to the fact that this is not the actual practice in most hospital EDs and ICUs, where the approach to antibiotic selection is “one size fits all,” and every time a patient “crashes,” they call it sepsis. The sound approach is that in the absence of septic shock, attention should be paid to the likely source of infection, which would suggest the most likely pathogens to be addressed, in lieu of “treating for everything.”

With all that being said, the infectious diseases specialist may have the “best eye” for beholding sepsis, and he or she surely needs to be involved in any and all patients considered to be suffering from sepsis or septic shock.

Disclosures: Bush and Kaye report no relevant financial disclosures.