The drive to standardize clinical practice for sepsis

Aug. 24, 2016

In 2013, the state of New York passed “Rory’s Regulation,” a law requiring all state hospitals to enact formalized sepsis protocols for early recognition and treatment. This year, the Illinois Senate passed a similar law, and efforts have begun in Indiana and Pennsylvania to do the same. In the United Kingdom, the National Institute for Health and Care Excellence (NICE) issued a guideline to develop a code for sepsis that is similar to Code Blue for cardiac resuscitation. Patient advocacy groups in the United States have petitioned Congress and the Centers for Disease Control and Prevention (CDC) to also adopt a nationwide Sepsis Protocol.

Awareness of sepsis today is the greatest it has ever been—and with sepsis, awareness saves lives. This awareness has led to efforts to ensure that all sepsis patients are treated quickly, including the Centers for Medicare and Medicaid Service (CMS) guidelines for Severe Sepsis and Septic Shock Quality Measures.

These efforts seek to standardize clinical practice and are typically based on the groundbreaking 2001 New England Journal of Medicine paper: “Early Goal-Directed Therapy (EGDT) in the Treatment of Severe Sepsis and Septic Shock.”1 This paper is the foundation of the Surviving Sepsis Campaign (SSC) sepsis definition and intervention bundles.

The SSC bundle

The three-hour SSC bundle requires an initial measurement of serum lactate, drawing blood cultures prior to antibiotics, and broad spectrum antibiotics within three hours of ED admission, along with the treatment of hypotension and/or in the presence of elevated lactic acid of >4 mmol/L. It was predicated upon the definition of sepsis as systemic inflammatory response syndrome (SIRS) plus a documented infection, along with clinical response to insult, as well as at least two of the following symptoms: elevated temperature, tachycardia, tachypenea, or elevated white blood cell counts.

As we push for standardized care, however, it’s vital that we allow flexibility in our laws and guidelines so that we can adopt new and better tools to diagnose and treat sepsis. Sometimes, this flexibility has been lacking.

For example, the sepsis definition above was recently changed, given the inadequate sensitivity and specificity of SIRS criteria for identifying sepsis,2 yet CMS continues to rely on the old definition. Insisting that blood cultures be drawn prior to antibiotics is a good policy, but it ignores the reality that more than 60 percent of cultures from sepsis patients come back negative or inconclusive. Another example: the dependence on lactic acid as the only biomarker in many state guidelines ignores the fact that a more sensitive biomarker has been developed and is now widely used by U.S. hospitals to supplement lactic acid in order to help critical care doctors make better-informed treatment choices.

Procalcitonin as a biomarker

Lactic acid is helpful in risk stratification, and indicates tissue perfusion. It is an indicator of tissue hypoxia, but that is a process that occurs only when sepsis has already begun to cause organ failure. So we at Moses Cone Hospital, and many other hospitals, added a procalcitonin (PCT) assay to our sepsis protocol to improve early and rapid detection of sepsis, and it has made a tremendous difference. Lactic acid and PCT are synergistic in detection of sepsis.

When PCT is added, the sensitivity and specificity of sepsis diagnosis can be significantly increased compared with conventional clinical and laboratory parameters.3 In practice, PCT along with lactic acid measurement has improved our ability to assess risk in sepsis patients, provide faster intervention, and improve outcomes.

So, in many respects the current clinical practice does not reflect guidelines, quality metrics, or state law. In this case, that’s a good thing: we’re continuing to adapt and improve without being held back by an effort to create uniform practice guidelines that can sometimes be overly prescriptive.

Antibiotic resistance

We are also about to embark on a national initiative by CMS at the beginning of 2017 to curtail the overuse of antibiotics, specifically broad-spectrum antibiotics which are recommended for suspected sepsis patients. Will the attempt to standardize sepsis clinical practice and the emphasis on antibiotic stewardship come into conflict? I hope not. They certainly are not mutually exclusive goals; after all, resistant pathogens are often what kill sepsis patients. But again, to succeed in both efforts, we need flexibility.

The tool that helps us detect sepsis faster is also what we use to make sure patients can be taken off IV antibiotics and shorten drug duration safely: the PCT molecule plays a significant role in antibiotic stewardship. The induction and release of PCT is highly specific to bacterial infections. In fact, PCT production is blocked in viral infections. Knowing that a suspected case of sepsis is most likely caused by bacteria gives clinicians an advantage when making early treatment decisions—decisions that very often can make the difference between life and death.4-5

It has been shown that a PCT algorithm for antibiotic discontinuation is a cost-effective means of reducing antibiotic exposure in patients with sepsis, compared to current practice.6 We use a similar algorithm based on PCT kinetics to discontinue antibiotics and have been very pleased with the significant reduction in antibiotic use.

The involvement of government in setting uniform standards for defining and treating sepsis is crucial to our overall goal. In the clinical setting, we are helping to refine and perfect the protocols.


  1. Rivers E, Nguyen B, Havstad S. et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. NEJM. 2001;345:1368-1377.
  2. Singer M, Deutschman, CS, Seymour CW, et al. The third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA. 2016;315(8):801-810.
  3. Harbarth S, Holeckova K,, Froidevaux C, et al. Diagnostic value of procalcitonin, interleukin-6, and interleukin-8 in critically ill patients admitted with suspected sepsis. Am J Respir Crit Care Med. 2001;164(3):396-402.
  4. Christ-Crain M, Müller B. Procalcitonin in bacterial infections—hype, hope, more or less? SwissMedWkly. 2005;135:451–460.
  5. Linscheid P, Seboek D, Nylen ES, et al. In vitro and in vivo calcitonin I gene expression in parenchymal cells: a novel product of human adipose tissue. Endocrinology. 2003;144(12): 5578–5584.
  6. Kip M, Kusters R, IJzerman, MJ; Steuten LMG. A PCT algorithm for discontinuation of antibiotic therapy is a cost-effective way to reduce antibiotic exposure in adult intensive care patients with sepsis. J Med Econ. 2015;18(11): 944-953.

Daniel J. Feinstein, MD, FACP, is affiliated with the Cone Health System in Greensboro, North Carolina.