Toward Smarter Lumping and Smarter Splitting: Rethinking Strategies for Sepsis and Acute Respiratory Distress Syndrome Clinical Trial Design

Abstract

Both quality improvement and clinical research efforts over the past few decades have focused on consensus definition of sepsis and acute respiratory distress syndrome (ARDS). Although clinical definitions based on readily available clinical data have advanced recognition and timely use of broad supportive treatments, they likely hinder the identification of more targeted therapies that manipulate select biological mechanisms underlying critical illness. Sepsis and ARDS are by definition heterogeneous, and patients vary in both their underlying biology and their severity of illness. We have long been able to identify subtypes of sepsis and ARDS that confer different prognoses. The key is that we are now on the verge of identifying subtypes that may confer different response to therapy. In this perspective, inspired by a 2015 American Thoracic Society International Conference Symposium entitled "Lumpers and Splitters: Phenotyping in Critical Illness," we highlight promising approaches to uncovering patient subtypes that may predict treatment responsiveness and not just differences in prognosis. We then discuss how this information can be leveraged to improve the success and translatability of clinical trials by using predictive enrichment and other design strategies. Last, we discuss the challenges and limitations to identifying biomarkers and endotypes and incorporating them into routine clinical practice.

ARDS: challenges in patient care and frontiers in research

“…in whom benefit outweighs harm) to the treatment in the included population. It is the premise of precision medicine to enrich this group as much as possible with patients with a responsive phenotype (also called predictive enrichment) [58]. The selection of the right patient for the right treatment is one the largest challenges for the coming decade [59,60].…”

Balanced Crystalloids versus Saline in the Intensive Care Unit. The SALT Randomized Trial

“…To definitively evaluate the effect of balanced crystalloids versus saline on patient-centered outcomes, a large, randomized trial that carefully accounts for differences in baseline risk of AKI (8), volume of crystalloid received (7), and underlying pathophysiology (9)(10)(11)(12) among patients in the intensive care unit (ICU) is required. Such a trial faces numerous logistical challenges, including the need to enroll thousands of patients, deliver the assigned crystalloid in a time-sensitive manner, and collect detailed data on the exact amounts of crystalloid administered, the physiological effects (e.g., serum chloride), and outcomes.…”

The intensive care medicine research agenda on septic shock

“…Similarly, other immunomodulatory drugs such as intravenous immunoglobulins have been discarded based on lack of overall outcome effect [68]. We should re-evaluate such treatment 'failures' by using predictive or prognostic enrichment [69]. Treatment-responsive sub-phenotypes have been suggested for ARDS [70] and sepsis [71], and these need to be explored further.…”