What could be wrong about a campaign to promote sepsis survival? Looking back on the history of the Surviving Sepsis Campaign (SSC), just about everything. Understand, though, this knowledge is borne with the benefit of hindsight; there are lessons to be learned for all of us.

The initial SSC recommendations in 2004 were an attempt by many individuals in critical care and other professional societies (including ACEP) to improve sepsis care on the heels of what finally appeared to be new lifesaving interventions.¹

Although introduced and received with much enthusiasm, the SSC recommendations were soon called into question in a New England Journal of Medicine article critical of pharma sponsors that made products associated with these recommendations, particularly Eli Lilly who made Xigris.² Looking back, even the least cynical would acknowledge that many of the strongly recommended approaches from the initial 2004 and 2008 guidelines were later shown to be not only ineffective or unnecessary but also dangerous.^1,3 Specifically, the following were recommended in 2004 and then later removed:

• Activated protein C (Xigris): Demonstrated ineffective, associated with an increased risk of bleeding, and withdrawn from the market (Xigris recommended against in 2012).
• Dopamine among first choices for fluid-unresponsive septic shock: Associated with more arrhythmias and a higher mortality rate than norepinephrine (norepinephrine recommended in 2012).
• Tight glucose control (<150 mg/dL): Associated with severe hypoglycemia and increased mortality compared with target glucose levels up to 180 mg/dL (goal changed to <180 mg/dL in 2012).
• Red blood cell transfusion to maintain hemoglobin >10 g/dL: Not found to be associated with improved outcomes compared with >7 g/dL (goal changed to 7–9 g/dL in 2008).
• Early goal-directed therapy (EGDT) resuscitation based on serial central venous O2 saturation assessments: Found to have no survival benefit compared with usual care (EGDT parameters not mentioned in 2016).

In retrospect, a clear theme of the original recommendations was that many were based on early, positive, but not well-validated results. For example, the EGDT recommendation was based on a single-center trial that involved 263 participants.⁴ While the Xigris trial was multicenter and involved 1,690 participants, the results had not been validated in another investigation at the time the SSC recommended it.⁵

In response to the remarkably rigorous multisite, multinational debunking of EGDT—first by the ProCESS trial and later by the ARISE and ProMISe trials, with almost 5,000 total participants—the SSC responded by pointing out the 18 percent mortality in the usual care arm “illustrates a dramatic change in the management and outcomes of patients with septic shock” compared with the higher mortality rate in the original EGDT trial.⁴ Temporal associations of SSC bundle compliance and lower mortality rates were also offered as support of SSC efforts.

Just as we should not get too far out in front with recommendations based on exciting but insufficient evidence, we should also be cautious about overstating cause and effect from temporal associations. In other words, just because it rained the night before and you woke up with frogs on your lawn, doesn’t mean it rained frogs.

To wit, Lindenauer et al demonstrated that coincident with the SSC, more patients, including low-risk ones, were being given a sepsis diagnostic code.⁶ For example, patients with pneumonia who were at an intermediate risk of death had been shifted from the “pneumonia bucket” to the “sepsis bucket,” lowering the mortality rates of both. In reality, though, sepsis survival rates had not changed.

Sepsis and severe sepsis diagnosis–related group codes are also associated with significantly higher payment than pneumonia codes alone. In addition, it’s up to the physician’s judgment whether the patient has sepsis or just systemic inflammatory response syndrome (SIRS), and all that’s required is documenting “sepsis” in the notes. Severe sepsis requires organ dysfunction, including an elevated lactate alone. The attention brought to sepsis by the SSC likely promoted earlier recognition, although we do not know the extent to which SIRS and then lactate screening led to unnecessary care and costs. And Centers for Medicare and Medicaid Services, thank you for the new sepsis core measure requirements in time for this year’s flu season, especially the lower lactate threshold of 2 mmol/L. This new directive illustrates the trade-off of enhanced screening to catch a few cases of bacterial sepsis earlier and the unintended consequence of excessive care for many stable but dehydrated patients with a benign viral illness.

What remains of SSC recommendations? Primarily fluid resuscitation, now at 30 cc/kg initially and then additional fluid based on further assessments of perfusion, and timely antibiotics. However, even fluid resuscitation is now under debate and study.

The current fluid strategy promoted by the SSC, based largely on the EGDT bundle, is typically with total amounts of 50–70 cc/kg (eg, 5 L) in the first six hours of care.⁷ This liberal fluid approach may be pressor-sparing and limit complications from hypoperfusion. Alternatively, a restrictive fluid approach of <30 cc/kg (eg, ≤2 L) in the first six hours, which relies on earlier use of vasopressors, may prevent complications from tissue edema that interfere with oxygen delivery and organ function. However, such a change will need to consider any increased risk of digital or limb amputations, which may be associated with expanded use of vasopressors.

This may sound crazy, but there are several lines of evidence that support a restrictive fluid approach, including a randomized controlled trial of children with severe malaria, a severity-adjusted analysis of 23,513 septic adults that found each liter beyond five associated with a mortality increase, and a recent randomized controlled trial of adults with septic shock showing significantly improved survival among those getting 2 versus 3.5 L in the first six hours.^8-10 A randomized trial of a liberal versus restrictive fluid approach for septic ED patients is currently being planned by the Prevention and Early Treatment of Acute Lung Injury network.

I asked Peter DeBlieux, MD, an emergency medicine and critical care specialist at Louisiana State University in New Orleans, for his perspective. He said, “Despite some missteps, the best aspect of SSC is promoting recognition; early recognition of sepsis means sooner antibiotics, source control, and care coordination with consultants. Continued recognition of the need for research to improve outcomes for this major killer is critically important.”

One of my mentors once told me it’s best to be neither the first nor the last to embrace an innovation. Unfortunately, in many ways, we’re back to where we started with sepsis.

References

1. Dellinger RP1, Carlet JM, Masur H, et al. Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock. Intensive Care Med. 2004;30(4):536-555.
2. Eichacker PQ, Natanson C, Danner RL. Surviving sepsis—practice guidelines, marketing campaigns, and Eli Lilly. N Engl J Med. 2006;355(16):1640-1642)
3. Dellinger RP, Levy MM, Carlet JM, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Intensive Care Med 2008;34(1):17-60.
4. Rivers E, Nguyen B, Havstad S, et al.Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001;345(19):1368-1377.
5. Bernard GR, Vincent JL, Laterre PF, et al. Efficacy and safety of recombinant activate proten C for severe sepsis. N Engl J Med. 2001;344(10):699-709.
6. Lindenauer PK, Lagu T, Shieh MS, et al. Association of diagnostic coding with trends in hospitalizations and mortality of patients with pneumonia, 2003-2009. 2012;307(13):1405-1413.
7. Rhodes A, Evans LE, Alhazzani W, et al. Surviving Sepsis Campaign: international guidelines for management of sepsis and septic shock: 2016. Crit Care Med. 2017;45(3):486-552.
8. Maitland K, Kiguli S, Opoka RO, et al. Mortality after fluid bolus in African children with severe infection. N Engl J Med 2011;364(26):2483-2495.
9. Marik PE, Linde-Zwirble WT, Bittner EA, et al. Fluid administration in severe sepsis and septic shock, patterns and outcomes: an analysis of a large national database. Intensive Care Med 2017;43(5):625-632.
10. Andrews B, Semler MW, Muchemwa L, et al. Effect of an early resuscitation protocol on in-hospital mortality among adults with sepsis and hypotension: a randomized clinical trial. JAMA. 2017;318(13):1233-1240.

Dr. Talan is professor of medicine in residence (emeritus) at the David Geffen School of Medicine at UCLA and chairman emeritus of the department of emergency medicine and faculty in the division of infectious diseases at Olive View-UCLA Medical Center in Los Angeles.