Defining Severe Sepsis: Is It Time to Update the Criteria?

This is Andy Shorr from George Washington University in Washington, DC, with the Pulmonary and Critical Care Literature Update. I want to discuss a new study by Kaukonen and colleagues^[1] that was published in the April 23 issue of the New England Journal of Medicine. This article addresses the definition of severe sepsis.

Historically, the definition of severe sepsis has been based on the presence or absence of systemic inflammatory response syndrome (SIRS) criteria.^[2] The definition requires at least two SIRS criteria to be present in the setting of known or suspected infection. The SIRS criteria are notoriously nonspecific, however, and include heart rate, respiratory rate, white blood cell count, temperature, and so forth. On the other hand, the vocabulary that existed before the 1992 consensus document that defined sepsis based on the SIRS criteria was a morass. People were using the terms "bacteremia" and "sepsis" interchangeably, and thus clinical trials could not be conducted in a systematic fashion that assured enrollment of homogeneous groups of patients. This led to the consensus conference in 1992, which developed a definition of severe sepsis and septic shock that relied on the presence or absence of the SIRS criteria, as a first step. (Many clinical trials for severe sepsis and septic shock have required at least three criteria, and not two, to enrich the study population and make sure that the disease state of concern is the one being studied.)

A Different Question

These authors asked a different question: What are the actual sensitivity, specificity, and screening characteristics of the SIRS criteria for the definition of sepsis? That question raises another one, which is, what is the gold standard for defining sepsis?

These authors looked at an administrative database comprising more than1.2 million patients admitted to critical care units in Australia and New Zealand over a decade. They were trying to identify patients who had severe sepsis and septic shock based on the presence of organ failure and infection. I believe that all of us would agree on the validity of using infection and organ failure to define septic shock or severe sepsis. The researchers then went back and extracted all of the SIRS criteria that these patients met when they were admitted or at the onset of the syndrome to see how well the SIRS criteria identified patients who had SIRS-positive (two or more criteria) vs SIRS-negative (less than two criteria) severe sepsis.

If you think back to your own practices, we have all seen patients with severe sepsis who do not meet SIRS criteria because they are elderly or they are beta-blocked or immunosuppressed, but clearly they have distributive shock and an identifiable nidus of infection. We would not withhold antibiotics and therapy from those patients; we would treat them aggressively. We simply acknowledge in our own minds that this is essentially SIRS-negative sepsis. You have to be a clinician applying a definition; you cannot just be an automaton.

Results Suggest That SIRS Criteria Miss Many Patients With Sepsis

From this dataset of 1.2 million people, these investigators identified about 100,000 patients who had acute infection and organ failure. They then went back and looked at how many met the SIRS criteria and how many did not. They found that about 1 in 8 patients (12%) had SIRS-negative severe sepsis or septic shock. That is huge. That suggests that the screening criteria or the definition we use is a poor test in terms of sensitivity. We are missing 1 in 8 patients.

Why is that important? It is important because many hospital protocols recommend initiation of antibiotic therapy promptly when patients meet the SIRS criteria, because we know that initial appropriate antibiotic therapy administered in a timely manner is what saves lives. And patients who do not meet the criteria but nonetheless have septic shock will be at an increased risk for death if they are not treated aggressively with antibiotics.

Testing the New Definition

How do we really know that these SIRS-negative patients had severe sepsis or septic shock? To externally prove that their definition of severe sepsis—organ failure and acute infection—was operationally useful, the authors compared the SIRS-negative and SIRS-positive patients in terms of their illness trajectories and outcomes during this time period. They found that patients with SIRS-negative sepsis had better overall outcomes than patients with SIRS-positive sepsis. They also saw that over time, as mortality rate fell in patients with SIRS-positive sepsis, so did the mortality rate in patients with SIRS-negative sepsis. Patterns of discharge and patterns of mortality were similar in the SIRS-positive vs SIRS-negative septic patients, in terms of how they changed over time. These similarities suggested that the investigators were capturing a group of patients with sepsis who are at a lower risk for death but otherwise had similar epidemiologic trends and trajectories. This internally confirms that their findings were not simply an academic or administrative phenomenon in these patients with SIRS-negative septic shock.

When the authors looked more precisely at which SIRS criteria were most often met, they found that these were heart rate and respiratory rate criteria. Not surprisingly, the white blood cell count criterion was often not met by patients with SIRS-negative sepsis. We have all taken care of patients who do not mount a white blood cell response or develop a bandemia in response to infection for whatever reason, but we know when we see them that they absolutely meet criteria for septic shock and require antibiotics and fluids, because of distributive changes.

Thus, by conducting that external check of the data and showing that the patterns of SIRS-negative and SIRS-positive sepsis are similar and consistent over time, these investigators have documented that they are studying the disease state they want to study.

This is important data that show, first of all, that outcomes from severe sepsis are getting better, whether it is severe sepsis, SIRS-positive sepsis, or SIRS-negative sepsis. More important, this study shows that there are patients who need urgent critical care because they have septic shock but do not meet the SIRS criteria. We cannot forget about them or fail to bring to bear all of the tools in our armamentarium for treating severe sepsis and septic shock.

This is a very thought-provoking article. I am certain that it will change guidelines and definitional approaches. It certainly has implications for quality control and administrative issues at hospitals. I urge you to look at this article.

This is Andy Shorr from Washington, DC.

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