Sepsis is the leading cause of death by infection and one of the largest contributors to the global burden of disease. Placing tremendous financial strain on hospitals and health systems worldwide, the optimal treatment strategy for patients with sepsis has long been an area of intense inquiry. The Rivers et al trial (N Engl J Med. 2001;345:1368-1377) in the early 2000s introduced the notion of resuscitating septic patients to specific target end points. While larger, more recent trials—PRoCESS (ProCESS Investigators, et al. N Engl J Med. 2014;370:1683-1693), ARISE (ARISE Investigators, et al. N Engl J Med. 2014;371:1496-1506), and PRoMISE (Mouncey et al. N Engl J Med. 2015;372:1301-1311)—have reversed the findings described by Rivers of rigid adherence to finite values of central venous pressure, mean arterial pressure, and venous oxygen saturation as consecutive end points, there remains broad consensus that patients with septic shock require early and aggressive intervention. Yet, on the question of how best to guide those resuscitative efforts, and to what end, the consensus remains elusive.
Hernández et al (JAMA. 2019;321:654-664) addressed that very question in a multicenter randomized trial in which they compared two resuscitative targets: the normalization of blood lactate and the normalization of peripheral perfusion as quantified by capillary refill time. Using 28-day mortality as their primary end point, they assigned patients with septic shock to one of two groups using the same 8-hour resuscitative algorithm, which included fluid boluses, vasopressors, and inotrope support to treat inadequate perfusion. Treatment of the groups differed only in the method of determining when perfusion was adequate and therefore when resuscitative therapy could be stopped.
After enrolling 424 patients over one year across 28 sites in five South American countries, the authors concluded that their findings “do not support the use of a peripheral perfusion-targeted strategy in patient with septic shock.” This statement reflects but does not fully capture the significance of the nonsignificant 8.5% absolute decrease in mortality in patients targeted with normalization of peripheral perfusion as opposed to normalization of blood lactate (34.9% vs. 43.4%; hazard ratio, 0.75; 95% CI, 0.55%-1.02%; p = 0.06).
While the study failed to demonstrate the 15% absolute mortality reduction it sought as its primary outcome, there was significantly less organ dysfunction at 72 hours in the peripheral perfusion group, and their lactate levels were lower at 48 and 72 hours than those in the lactate group.
While trending toward better outcomes, the peripheral perfusion group also received 400 mL less fluid, suggesting a need to rethink the long-held dogma that aggressive fluid resuscitation is an answer to sepsis. Had the authors sought a more modest mortality difference than one approaching the 16% shown in the Rivers trial, as was sought in the PRoMISE, ARISE, and PRoCESS trials (8%, 7.6%, and 6%-7%, respectively), they might have adequately powered their study with triple the patients and shown that an easy-to-use, resource-independent, less costly method for targeting the treatment of this global disease was, in fact, superior.
Coauthors of this installment of Concise Critical Appraisal:
Cameron Kyle-Sidell, MD, is a critical care medicine fellow at the University of Maryland Medical Center, Baltimore, Maryland, USA.
James H. Lantry III, MD, is an assistant professor of emergency and critical care medicine and the associate program director of the Critical Care Fellowship at the University of Maryland Medical Center in Baltimore, Maryland, USA. Dr. Lantry is an editor of Concise Critical Appraisal.