Will This Be the Holy Grail for Sepsis?

Hello. I'm Paul Auwaerter for Medscape Infectious Diseases, speaking from the Johns Hopkins School of Medicine.

As I just finished rounding in our ICU, seeing critically ill patients reminded me that incremental progress had been made in sepsis, but we remain desperate to help our patients who are profoundly ill despite supportive care and appropriate antimicrobial therapy.

Approaches to severe sepsis and septic shock continue to evolve with strategies put forward and discarded regularly. The focus for distributive shock is now on timely fluid resuscitation, antibiotics, and, if necessary, vasopressor agents. However, the holy grail seems to have always been to intervene in the inflammatory cascade, shutting down what is often a deleterious set of forces that contribute to death. Complicating factors have been that sepsis is such a heterogeneous condition, not only in the infectious causes but in the host immune responses, yet all randomized clinical trials use a very firm endpoint: mortality.

There is a veritable graveyard of interventions that have never proven truly effective. Those of you who have viewed some of my videos know that I like looking back as well as forward. I remember as a house officer and infectious diseases fellow in the 1980s and 1990s the excitement and promise of antibody-based interventions led by Elizabeth Ziegler^[1] at the University of California, San Diego. Using sera and, later, monoclonal antibodies against gram-negative lipopolysaccharide endotoxin in both mice and human studies, it looked like there was something possibly groundbreaking in sepsis care. However, despite some initial successes, there was never enough convincing data to suggest sufficient bang for the buck with respect to mortality reduction.

Many of us remember the sepsis drug that did make it to market—drotrecogin-alpha (Xigris)—the recombinant activated protein C molecule meant to reduce vascular inflammation. It did have a small effect on mortality, but much like the Ziegler studies, the clinical trials were often criticized and challenged based on both study design and interpretation of outcomes. The drug was withdrawn from the market in 2011.

I was reminded of these interventions reading the recent JAMA article by Vincent and colleagues,^[2] who looked at using a recombinant human soluble thrombomodulin to see if it led to an improvement in patients with sepsis-associated coagulopathy. Compared with placebo, patients receiving the recombinant thrombomodulin unfortunately had more bleeding and had no change in 28-day mortality.

However, many efforts continue, using varied approaches to interrupt the sepsis inflammatory cascade. These include intravenous angiotensin II in the treatment of high-output septic shock,^[3] with some trials showing trends towards improved 28-day survival but a higher risk for thrombotic events. Perhaps the most surprising is the return of high-dose vitamin C, not as an anticancer therapy but employed with corticosteroids and thiamine in sepsis, and it appears preliminarily to suggest benefit.^[4]

However, if you were a gambler [considering] the nature of sepsis and its host immune responses, it would be a high-risk bet that a one-drug-fits-all approach will succeed. Instead, I think if a breakthrough were to occur in therapeutic interventions for septic shock, it would be something incorporated within the concept of precision medicine. If we more precisely understand how to best target immunomodulation in a particular patient, this could be the recipe for success. Perhaps instead of targeting the inflammatory cascade, success may come from interrupting the driver much as Dr Ziegler conceived in the early 1980s.

One recently published approach shows some promise in this vein. Laterre and colleagues^[5] examined a novel liposomal agent called CAL02 that binds bacterial virulence factors. They studied patients with severe community-acquired pneumococcal pneumonia. This small trial enrolled only 19 patients, with 13 in the treatment arm. The CAL02 group had fewer severe adverse events than the placebo group and had a 65% lower organ failure assessment score. Such tactics herald a new approach that deserves further study, but to anyone who cared for patients in the ICU, effective help cannot come soon enough.

Thank you for listening.

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