It's been nearly a year since the European Society of Intensive Care Medicine and the Society of Critical Care Medicine introduced SEPSIS-3—a new consensus definition for sepsis—and the cleft between adoption in research and clinical practice is widening. While GlobalData believes that SEPSIS-3 has already begun to improve clinical research, its impact on how clinicians manage their patients has not yet been felt due to a healthy skepticism with regards to its utility compared with the older definitions and understanding of sepsis (SEPSIS-2).
In January 2017, the Surviving Sepsis Campaign Society (SSCS) released an official update on their 2012 treatment guidelines. SEPSIS-3 defines sepsis as a life-threatening organ dysfunction caused by a dysregulated host response to infection, thereby moving away from the concept that sepsis is a systemic inflammation response syndrome (SIRS) with infection. At the same time, SEPSIS-3 simplified the disease definition by removing the term severe sepsis, as sepsis is now already defined as life-threatening organ dysfunction, which if the patient is not responsive to fluid resuscitation or presence with hyperlactatemia is termed septic shock.
Although the understanding of sepsis has changed significantly in SEPSIS-3, the treatment recommendations outlined in the SSCS guidelines have only changed marginally. Among the most important changes, early goal-directed therapy (EGDT) is no longer recommended for initial resuscitation, the use of dynamic (pulse or stroke volume variations) over static measures (intravascular pressure or volumes) is recommended to predict fluid responsiveness, antibiotic interventions should be administered as soon as possible, and for the first time, antibiotic combination therapy is recommended in patients with septic shock.
GlobalData notes that the new SSCS treatment guidelines pay little attention to the clinical definition of sepsis and instead refer to the current SEPSIS-3 definitions. While this signifies further alignment with SEPSIS-3, the Centers for Medicare & Medicaid Services (CMS) treatment guidelines have not yet adopted the current understanding of sepsis as outlined in SEPSIS-3. This failure by CMS to rapidly adopt SEPSIS-3 reflects clinicians’ concern about delayed diagnosis, as the new sepsis criteria have until recently only been validated in retrospective database studies. Because US hospitals are bound under monetary penalty to apply current CMS reporting requirements on severe sepsis and septic shock, many physicians still have not adopted the evidence-based sepsis definition of SEPSIS-3 in clinical practice. Furthermore, coding and billing are based on current ICD-10-CM codes, which still include severe sepsis.
Quick sepsis organ failure assessment
The disconnect of the current thinking of sepsis is predominantly felt in the emergency departments, where the new definitions have created public outcry over fears that diagnosis might be delayed by abandoning the concept of sepsis as progressive disease from SIRS with infection, towards severe sepsis and septic shock. In an effort to alleviate these concerns, the SEPSIS-3 consortium suggested the use of quick sepsis organ failure assessment (qSOFA), defined by a respiratory rate of 22/min or more, altered mental status, and a systolic blood pressure ≥100mmHg, as a tool to identify patients with increased mortality risk.
In January 2017, a prospective clinical study validated qSOFA as appropriate in the early detection of sepsis patients in everyday clinical practice, using in-hospital mortality data as outcome measure. In this prospective study, 879 patients treated with suspected infection in 30 emergency departments for a four-week period across France, Spain, Belgium, and Switzerland demonstrated better prediction of in-hospital mortality for qSOFA than compared to SIRS and severe sepsis, with areas under the receiver curve (AUROCs) of 0.80 (95% CI, 0.74–0.85) versus 0.65 (95% CI, 0.59–0.70) for both SIRS and severe sepsis (p <0.001; incremental AUROC, 0.15; 95% CI, 0.09–0.22), respectively.
Sepsis drug discovery has seen an enormous amount of late-stage failure, with over 100 failed randomized clinical trials. GlobalData believes that the newly validated SEPSIS-3 definition holds great promise in bringing new treatment options to market. GlobalData expects that these treatment options have great potential of changing the current treatment paradigm and that current and future efforts of redefining sepsis will aid to stratify patients towards one of the above outlined treatment options, thereby breaking the streak of bad clinical outcomes. Improvements in sepsis etiology and physiology will continue to shape the treatment landscape in sepsis. While GlobalData sees a bright prospect for future clinical research in sepsis using the new SEPSIS-3 definitions, the impact on everyday clinical practice remains uncertain.