Anja Kathrin Jaehne

Early biomarker activity in severe sepsis and septic shock and a contemporary review of immunotherapy trials: not a time to give up, but to give it earlier.

ABSTRACT Improving time to diagnosis and intervention has positively impacted outcomes in acute myocardial infarction, stroke, and trauma through elucidating the early pathogenesis of those diseases. This insight may partly explain the futility of time-insensitive immunotherapy trials for severe sepsis and septic shock. The aim of this study was to examine the early natural history of circulatory biomarker activity in sepsis, relative to previous animal and human outcome trials. We conducted a literature search using PubMed, MEDLINE, and Google Scholar to identify outcome trials targeting biomarkers with emphasis on the timing of therapy. These findings were compared with the biomarker activity observed over the first 72 h of hospital presentation in a cohort of severe sepsis and septic shock patients. Biomarker levels in animal and human research models are elevated within 30 min after exposure to an inflammatory septic stimulus. Consistent with these findings, the biomarker cascade is activated at the most proximal point of hospital presentation in our patient cohort. These circulatory biomarkers overlap; some have bimodal patterns and generally peak between 3 and 36 h while diminishing over the subsequent 72 h of observation. When this is taken into account, prior outcome immunotherapy trials have generally enrolled patients after peak circulatory biomarker concentrations. In previous immunotherapy sepsis trials, intervention was delayed after the optimal window of peak biomarker activity. As a result, future studies need to recalibrate the timing of enrollment and administration of immunotherapy agents that still may hold great promise for this deadly disease.

Early Liberal Fluid Therapy for Sepsis Patients Is Not Harmful: Hydrophobia Is Unwarranted but Drink Responsibly

Critical Care Medicine www.ccmjournal.org 2263 EARLY INTERVENTIONS IMPROVE OUTCOME Sepsis in the year 2016 remains the most expensive disease treated in hospitals and is the most common cause of in-hospital deaths in the United States (1). However, over the last 15 years, since the introduction of early goal-directed therapy (EGDT) and the Surviving Sepsis Campaign (SSC), there has been a consistent and historic reduction in mortality (2). The reduction from a historic mortality of 46.5% to less than 30% was validated when a trio of multinational trials named Protocolized Care for Early Septic Shock (ProCESS), Australasian Resuscitation in Sepsis Evaluation (ARISE), and Protocolized Management in Sepsis (ProMISe) “compared” various forms of resuscitation strategies (2, 3). This independently obtained historic mortality of 46.5% from an international task force of experts is identical to that of the original EGDT trial (2). Thus, it is absolutely clear that a protocolized approach consisting of early detection (lactate and fluid challenge), antibiotic therapy, source control, prevention of sudden cardiopulmonary events, and early hemodynamic optimization improves outcomes. Even with unprecedented and replicated mortality benefit, many have proposed to dissemble the original EGDT trial and its components (4). ProCESS, ARISE, and ProMISe attempted to replicate and examine the efficacy of EGDT and have shown all time low mortalities, equal mortality reduction in all arms with no harm of EGDT. For some, these trials have made EGDT synonymous with an early liberal fluid strategy and its negative consequences (5–8). In rebuttal to our distinguished colleagues Genga and Russell (9); we advocate that treating early sepsis is not a time to be hydrophobic. Early fluid therapy in the context of a physiologically based protocol such as EGDT improves mortality for severe sepsis and septic shock.

Protocolized Early Sepsis Care Is Not Only Helpful for Patients: It Prevents Medical Errors.

“When I was entangled in my first medical error, I played an unexpected role: I was a thirty-three-year-old son trying to save my mom’s life....On the line was an emergency physician in the Wisconsin town where I’d grown up, telling me my mom was sick with sepsis at 9 am. He sounded harried, and I heard papers rustling in the background....The condition is well known, is easily diagnosed, and has a clear and standard treatment protocol.... The first twenty-four hours of my mom’s hospitalization would be critical to saving her life. Studies of sepsis have shown that early and aggressive treatments during that time can make the difference between life and death.... The hospital now was twelve hours into its critical opportunity to halt her systemic infection.... My mom was moved to the ICU around midnight, fifteen hours after she’d arrived at the hospital. I figured I’d get a bit of rest once her central-line IV and other treatments were started..... By 1 am. I was panicking. The next time I saw my mom’s nurse, I asked about the treatment plan. Her response was a not-so-veiled criticism of my mom’s doctor. “We do have a sepsis treatment protocol,” she said, “but your mother’s doctor hasn’t ordered it.”....But, by the time the sepsis protocol was finally put in place, it was 8 am the next day. A total of twenty-three hours without appropriate treatment had passed since my mom had entered the hospital. She still had a chance to survive, but because of the squandered opportunity, it was a small one....Toward the end, in a final moment of brief lucidity, she opened her eyes and whispered, “I never got to say good-bye.” She was dead by the end of the week.... Today—and tomorrow—in hospitals across the nation, there are patients whose survival and well-being will depend on it. Their lives, like my mom’s, hang in the balance. With lives on the clock, and as hours and days tick away, we need to listen to every voice and do everything possible to avoid repeating terrible mistakes (1).”