Permpikul C, Tongyoo S, Viarasilpa T, et al. Early Use of Norepinephrine in Septic Shock Resuscitation (CENSER). A Randomized Trial. Am J Respir Crit Care Med. 2019 May 1;199(9):1097-1105. doi: 10.1164/rccm.201806-1034OC. (Original study)

Rationale: Recent retrospective evidence suggests the efficacy of early norepinephrine administration during resuscitation; however, prospective data to support this assertion are scarce. Objectives: To conduct a phase II trial evaluating the hypothesis that early low-dose norepinephrine in adults with sepsis with hypotension increases shock control by 6 hours compared with standard care. Methods: This single-center, randomized, double-blind, placebo-controlled clinical trial was conducted at Siriraj Hospital, Bangkok, Thailand. The study 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 =65 mm Hg, with urine flow =0.5 ml/kg/h for 2 consecutive hours, or decreased serum lactate =10% from baseline) by 6 hours after diagnosis. Measurements and Main Results: 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 the early norepinephrine group (93 vs. 192 min; P < 0.001). Shock control rate by 6 hours was significantly higher in the early norepinephrine group (118/155 [76.1%] vs. 75/155 [48.4%]; P < 0.001). The 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). Conclusions: Early norepinephrine was significantly associated with increased shock control by 6 hours. Further studies are needed before this approach is introduced in clinical resuscitation practice. Clinical trial registered with www.clinicaltrials.gov (NCT01945983) (CENSER trial).

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Discipline Area Score
Intensivist/Critical Care 6 / 7
Respirology/Pulmonology 5 / 7
Emergency Medicine 5 / 7
Comments from MORE raters

Emergency Medicine rater

This single site RCT, from Thailand, found early administration of IV norepinephrine to patients with presumed septic shock increased the patient's mean BP at 6 hours. It did not change important clinical outcomes, such as survival. This study will not change emergency medicine practice.

Emergency Medicine rater

This is an important study that may very well change the way we practice emergency critical care resuscitation of patients in septic shock, pending larger prospective studies. The study was under-powered to evaluate patient-important outcomes such as mortality and long-term morbidity but trended towards benefit of administering norepinephrine earlier.

Intensivist/Critical Care rater

This pilot phase II study of early norepinephrine administration to patients with sepsis and hypotension, without septic shock criteria, showed that hemodynamic situation is better controlled than without vasopressor therapy (less fluid used particularly). This is probably what many ED and ICU physicians already do, but it has to be assessed in a phase III RCT, with mortality as an outcome.
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