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May - 2019


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Early Use of Norepinephrine in Septic Shock Resuscitation (CENSER)

C Permpikul, S Tongyoo, T Viarasilpa, et al Am J Resp Crit Care Med, 2019, 199(9);1097-1105


This phase 2 single centre trial adds the next step to an important question - does the early commencement of low-dose norepinephrine in patients with septic shock resuscitation result in improved outcomes?

To date the evidence for this is based on animal models and retrospective data. This phase 2 double blind, placebo controlled RCT performed in Siriraj Hospital in Thailand randomised 310 adult patients reports as follows;

  • Participants: adults presented to ED with MAP<65 mmHg, met diagnostic criteria for septic shock for less than 1-hour
  • Treatments;
    • Early low-dose norepinephrine:0.05 ug/kg/min for 24 hrs without titration
    • Standard care: 5% dextrose as placebo
    • Care in both arms was in accordance with SSG
  • Baseline: 65 year age, BMI 22, 30% UTI / 25% pneumonia / 20% abdominal, initial MAP 56, lactate 3, temp 38C
  • Treatment: Median time from ED to norepinephrine was 93 min vs 192 min (p<0.001), 
  • Outcomes
    • Shock control (achievement of sustained mABP of at least 65 mm Hg + adequate tissue perfusion defined as UO >0.5 ml/kg/hr for 2-hours or decrease lactate 10%) at 6-hours was significantly different 
    • No difference in admission to ICU, no difference, or time to ICU or ward admission
    • No difference in MV, RRT, or day 28 mortality 
    • No difference in fluid administration. The only difference was increase in open label use of norepinephrine. 
    • There was a decrease in cariogenic pulmonary oedema (14.4% vs 27.7%, p=0.004) and new onset arrhythmias (11% vs 20% p=0.03) in the norepinephrine group 

Overall the introduction of low-dose norepinephrine at 1.5 hrs vs 3.1 hrs after presentation to ED with septic shock in adults was associated with improvement in surrogate outcomes of shock resolution, and lower incidence in cariogenic pulmonary oedema and new onset arrhythmias. There was no difference in organ failure, organ support incidence or recovery, and survival. This is phase 2, hypothesis generating, and may lead to larger phase 3 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.


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