Early Use of Norepinephrine in Septic Shock Resuscitation (CENSER): A Randomized Trial

Permpikul C, Tongyoo S, Viarasilpa T, Trainarongsakul T, Chakorn T, Udompanturak S. Am J Respir Crit Care Med. 2019 Feb 1. [Epub ahead of print] [CrossRef][PubMed]

A vocal minority of researchers have advised against delaying vasopressors in septic shock, arguing that norepinephrine, not intravenous fluid, as the most effective initial treatment to correct the loss of vascular tone ("vasoplegia") from septic shock. The authors conducted a Phase II trial evaluating the hypothesis that early low-dose norepinephrine in adults sepsis with hypotension increases shock control by six hours compared with standard care. This single-center, randomized, double-blind, placebo-controlled clinical trial was conducted at Siriraj Hospital, Bangkok, Thailand and enrolled 310 adults diagnosed with sepsis with hypotension. The patients were randomly divided into two groups: early norepinephrine (n=155) and standard treatment (n=155). The primary outcome was shock control rate (defined as achievement of mean arterial blood pressure >65mmHg, with urine flow >0.5mL/kg/h for 2 consecutive hours, or decreased serum lactate >10% from baseline) by 6 hours after diagnosis. The patients in both groups were well matched in background characteristics and disease severity. Median time from emergency room arrival to norepinephrine administration was significantly shorter in early norepinephrine group (93 vs.192 min; P<0.001). Shock control rate by 6 hours was significantly higher in early norepinephrine group (118/155 [76.1%] vs.75/155 [48.4%]; P<0.001). 28-day mortality was not different between groups: 24/155 (15.5%) in the early norepinephrine group versus 34/155 (21.9%) in the standard treatment group (P=0.15). The early norepinephrine group was associated with lower incidences of cardiogenic pulmonary edema (22/155 [14.4%] vs. 43/155 [27.7%]; P=0.004) and new-onset arrhythmia (17/155 [11%] vs. 31/155 [20%]; P=0.03). The authors conclude that early norepinephrine was significantly associated with increased shock control by 6 hours. A much larger U.S-based trial testing early vasopressors in septic shock (CLOVERS) is currently recruiting, with plans to enroll up to 2,300 patients and an expected completion date of June 2021.