Sooner, smarter—new strategies against sepsis

Ann Griswold, PhD

July 2013—When it comes to fighting sepsis, the ingenuity of the laboratory is indispensable.

At the front line of the fight are physicians, who largely rely on guidelines issued by the Surviving Sepsis Campaign. But where the SSC guidelines end, a critical phase of the fight begins.

Laboratories, as incubators of innovative technologies, are constantly formulating fresh ways to improve the accuracy and reporting of sepsis diagnoses, and to uncover essential details about the identities and antibiotic susceptibilities of offending pathogens. And at the end of the day, laboratories are in an ideal position to track the impact of new technologies on patient outcomes. In these three areas—diagnoses, details, and impact—laboratories are striking back against sepsis.

The SSC guidelines, updated in 2012 to reflect changes in the clinical landscape since the 2008 version was issued, harness the expertise of 30 clinical organizations worldwide in a bid to improve patient survival (Dellinger RP, et al. Crit Care Med. 2013;41[2]:580–637). According to the SSC, the use of evidence-based treatment regimens known as sepsis care bundles—groups of interventions performed in a certain time frame—could save as many as 400,000 lives if just half of the eligible patients are treated at 10,000 participating hospitals. The hope, of course, is that the actual numbers will far outrun this estimate.

The 2012 guidelines contain several key updates from previous versions, says first author R. Phillip Dellinger, MD, director of critical care at Cooper University Hospital and a professor of medicine at Cooper Medical School of Rowan University, Camden, NJ. Most of the updates pertain to clinicians and pharmacists, Dr. Dellinger notes, but a handful of recommendations are targeted to clinical laboratories. The new guidelines suggest using the 1,3 beta-D-glucan assay and the mannan and anti-mannan antibody assays when exploring candidiasis as a differential diagnosis.

New levels for certain physiologic targets, such as glucose, are also described in the updated guidelines. The SSC previously recommended moderate glycemic control, using insulin therapy as needed to keep blood glucose levels below 150 mg/dL. But the new guidelines account for recent findings that an upper limit of 180 mg/dL can be just as effective while also reducing the risk of hypoglycemia. “We’re now recommending more liberal glucose control because we think that if you try to keep it too low, you’ll induce hypoglycemia in too many patients and push outcomes in a negative direction,” Dr. Dellinger explains.

Most notably, the revised guidelines tighten the timeline for detecting sepsis and initiating antibiotic therapy. Though the guidelines have long emphasized the need to collect a patient blood sample before initiating therapy, Dr. Dellinger notes, the authors changed the wording in the 2012 guidelines to ensure that patients receive antibiotics promptly, as studies have shown a 7.6 percent drop in survival for every hour that antibiotics are withheld from a patient with septic shock. “You should never wait longer than 45 minutes to get a blood culture,” Dr. Dellinger says. “If you’ll have to wait more than 45 minutes to collect a culture sample, you should go ahead and empirically give antibiotics.”

Similarly, whereas previous guidelines allowed six hours from patient presentation to the first measurement of lactate, a telltale marker of severe sepsis and septic shock, the 2012 guidelines cut that time in half, recommending a first lactate measurement within three hours of presentation and again after six hours to determine if resuscitation efforts were successful.

“We suggest using lactate normalization as a target for resuscitation,” Dr. Dellinger explains. “If someone has severe sepsis and their initial serum lactate is elevated, you want to resuscitate them with fluids, normalize their blood pressure, ensure good oxygen levels, and increase tissue perfusion to totally normalize lactate—that’s a new recommendation for 2012.” To better accommodate the new recommendation, laboratories will need to use a rapid and robust lactate assay; some emergency departments may prefer the use of blood gas analyzers to measure lactate levels closer to the bedside.

Though lactate is a useful indicator of severe sepsis and septic shock, and has proved valuable to physicians, the biomarker’s utility is limited, says Alison Woodworth, PhD, director of esoteric chemistry and associate director of clinical chemistry, Vanderbilt University Medical Center, and assistant professor of pathology, microbiology, and immunology, Vanderbilt School of Medicine. “Essentially, lactate is released when your tissues start to lose oxygen. If it is elevated in a patient with systemic inflammation, it is likely that he or she has severe sepsis, but it is not very useful for finding patients early in the sepsis pathobiological process because they haven’t yet had significant organ failure or oxygen deprivation.”

Clinicians are faced with the impossible task of searching for sepsis among patients who present with bits and pieces of the condition: lethargy, general aches and pains, fever, shortness of breath, rapid heart rate, and other symptoms that mimic unrelated inflammatory ailments. Blood cultures can take from 16 hours to three days to reveal answers. Researchers like Dr. Woodworth are searching for biomarkers that can identify an infectious agent early in the process, and quickly.

There’s just one problem, Dr. Woodworth says: So far, the FDA has cleared only single biomarkers for use in guiding the early diagnosis of sepsis, before culture results are in. But patients with sepsis may present differently—physiological indicators vary—depending on the pathogen involved and whether the patient has comorbidities. “It’s becoming clear that one biomarker is not going to be the answer for diagnosing sepsis,” Dr. Woodworth says. “That’s where biomarker panels come in.”

The advantage of multimarker panels lies in their flexibility. “The idea is to identify patients at each stage of the sepsis cascade, from the early upregulation of proinflammatory cytokines to the eventual development of organ failure, so that clinicians can diagnose and treat patients more precisely,” she explains. “When you choose biomarkers that are upregulated at different phases and combine them into a prediction model, it provides far superior diagnostic strength compared with any single marker available right now.” Dr. Woodworth is developing a sepsis biomarker panel designed to run on an existing immunoassay platform, allowing for the rapid measurement of inflammatory markers within hours of an infectious insult. The possibilities are enticing, she says.

“If you had a panel that could distinguish among patients with sepsis, severe sepsis, septic shock, or an inflammatory response that is unrelated to infection, you could immediately triage these patients and treat them accordingly,” Dr. Woodworth explains. Conceivably, such a panel could be used throughout the course of a patient’s admission to track therapy response.

Though such panels are in development, they’re a long way from FDA approval and have not yet been optimized to identify specific pathogens. Dr. Woodworth is exploring the use of biomarkers to identify bacterial agents of community-acquired pneumonia. But even if her efforts succeed, laborious culture systems will continue to be in demand until researchers hit upon a method of using biomarkers to determine antibiotic susceptibility profiles, she notes.

In the meantime, the new SSC guidelines focus on the indicators available now. Two FDA-cleared biomarkers, procalcitonin and C-reactive protein, are included as part of the criteria for diagnosing sepsis (in line with the 2003 SCCM/ESCIM/ACP/ATS/SIS Sepsis Definitions Conference). Previous versions of the guidelines noted that procalcitonin, a peptide upregulated in response to proinflammatory cytokines, does not reliably distinguish patients with sepsis from patients with inflammatory conditions unrelated to infection. “We, however, now suggest the use of procalcitonin and other biomarkers, not as a reason to start antibiotics but as variables in the decision to stop,” Dr. Dellinger says, noting that recent literature has shown that low procalcitonin levels can guide discontinuation of antibiotic therapy during the recovery from sepsis.

Dr. Woodworth agrees that procalcitonin as well as CRP can inform the decision to discontinue antibiotic therapy, but she worries about their inclusion in the diagnostic criteria. That said, she notes the markers might offer additional value in predicting prognosis, as recent studies suggest that elevated procalcitonin and CRP concentrations are associated with increased mortality.

“The biomarkers that are available right now are OK, but they have a lot of limitations,” Dr. Woodworth says. “Sepsis is not one disease, like diabetes. It’s a syndrome that can be caused by many different things.” Multimarker panels, she says, are unsurpassed in their ability to capture this diversity.

When a patient presents with symptoms of sepsis, two sets of blood culture samples—one to support aerobic and another to support anaerobic growth—are collected within the first 45 minutes, and laboratory tests are ordered to assess levels of lactate, CRP, and procalcitonin. After that point, however, the SSC guidelines offer little guidance for clinical laboratories. In the hours and days that follow, physicians devote their efforts to resuscitating and stabilizing the patient, while clinical laboratories work to detect growth in culture, identify the pathogen, and determine antibiotic susceptibilities.

“In that way, the guidelines aren’t accounting for what happens after the first four to six hours,” says Donna M. Wolk, MHA, PhD, D(ABMM), system director of the microbiology laboratory at Geisinger Medical Laboratories, Danville, Pa., and director of the Center for Infectious Disease Diagnostics and Research at Weis Research Center. “Microbiology laboratory efforts can still save people’s lives after that point if we apply the right technology.” In particular, rapid reporting of blood culture results allows patients to transition from broad-spectrum antibiotics to less toxic and more targeted therapies that can improve outcomes, Dr. Wolk notes.

The importance of timely blood culture processing and reporting has not been addressed in the SSC’s guidelines, Dr. Dellinger says. “Perhaps that literature should be pursued in the next rendition of the guidelines. We did not have any clinical laboratory representation on the guidelines committee. That should also likely occur in the next revision.”

A recent Q-Probes study on the timeliness and accuracy of reporting preliminary blood culture results found that most laboratories achieve admirable turnaround times, with a median time of 45 minutes from detection of a positive blood culture to reporting of preliminary Gram stain results.

“The sooner you identify what the pathogen is and adjust the treatment, the better the outcome. Our study showed that laboratories by and large do a pretty good job of accomplishing that goal,” says study author Ron B. Schifman, MD, chief of diagnostics, Southern Arizona VA Healthcare System, and associate professor of pathology, University of Arizona College of Medicine.