Written by Clay Smith
This small single-center RCT showed that early administration of norepinephrine resulted in improvement in shock control* at 6 hours compared with standard therapy.
*Shock control = MAP >65 + urine output >0.5mL/kg/h for 2 consecutive hours, or decreased serum lactate >10% from baseline
Why does this matter?
Does starting norepinephrine earlier improve outcomes? Current recommendations are to give an adequate fluid challenge first and start pressors if that fails. What if we started pressors earlier? Retrospective data suggests this might be beneficial. The CLOVERS trial is a phase III study currently underway to answer this more definitively. Until then, this is encouraging news that early vasopressors may be of benefit.
CENSER - not just for incense anymore
This was a phase II, double blinded, placebo controlled RCT with 310 adults with sepsis and hypotension, MAP <65. Groups were well matched with randomization. They got either norepinephrine 0.05 μg/kg/min infused for a period of 24 hours without titration or an identical appearing bag started with IV fluid boluses. They were all given standard Surviving Sepsis treatments, including up to 30mL/kg isotonic fluid, source control, etc. If they remained hypotensive after fluid, open label pressors were started at the treating physician’s discretion. The primary outcome was measured 6 hours from the time of initial diagnosis and was called the “shock control rate,” defined above. As would be expected, norepinephrine was started much earlier in the treatment arm: 93 minutes vs 192 minutes in the controls. A little over half of the patients in each arm were finally admitted to the ICU; the rest went to the floor (though they allowed infusion of vasopressors on the general ward). For the primary outcome of shock control, the norepinephrine group fared better: 76.1% vs. 48.4% (OR 3.4; 95% CI, 2.09–5.53). The relative risk was 0.761/0.484 = 1.57; NNT = 4. There was no statistically significant difference in 28-day mortality: 24/155 (15.5%) in the norepinephrine group vs 34/155 (21.9%) in controls (p = 0.15); although, that trend is interesting. The norepinephrine group had statistically (and clinically) significantly fewer complications of cardiogenic pulmonary edema and new-onset arrhythmia, each occurring about half as often than controls. There were loads of exclusion criteria; so, this was a select group. Also, this was fairly small, single-center study, with half of the patients in each group well enough after treatment to go to the floor. They also used a non-standard composite for the primary outcome, though it does reflect macro and micro-circulation. Overall, I think starting pressors early is promising. Hopefully, the CLOVERS trial in progress will shed more light.
Early Use of Norepinephrine in Septic Shock Resuscitation (CENSER) : A Randomized Trial. Am J Respir Crit Care Med. 2019 Feb 1. doi: 10.1164/rccm.201806-1034OC. [Epub ahead of print]
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Reviewed by Thomas Davis