We all know hypotension is bad. But should we fill with fluids or rev up the heart with pressors. This begs the question does early norepi help prevent hypotension and mortality? Today’s quick hit article:
Permpikul C, et al. 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. PMID 30704260.
THE BREAK DOWN:
In this prospective double blinded intention to treat analysis RCT conducted in Thailand the authors found that early fixed dose norepinephrine (0.05 mcg/kg/min) allowed for faster time to the primary outcome of “shock control” by 6 hours after diagnosis of septic shock. Shock control was defined as achievement of a MAP >65 plus urine output (>0.5 ml/kg/hr) and a lactate that cleared by 10%. They found no clinical or statistical increase in limb or organ ischemia even when norepinephrine was administered by peripheral access during the patient’s entire hospitalization. Lastly, a secondary (hypothesis generating) outcome of 28 day mortality showed a difference of 5% in favor of the fixed dose norepinephrine group which would be nice if that were real and reproducible.
This was a very interesting phase II, double-blind, placebo RCT with intention to treat analysis. That looked to answer the question of “shock control” in septic shock. Shock control (A COMPOSITE OUTCOME) was defined as achievement of a MAP >65 mmHg plus urine output (>0.5 ml/kg/hr) and a lactate that cleared by 10%. The interesting part comes in from their inclusion/exclusion criteria. Keep in mind that the population studied is one of the biggest predictors of generalizability in a trial. They excluded patient if they met the criteria of septic shock for MORE THAN 1 hour before randomization! I’m not really sure why they would do that. They screened 456 patients and excluded 136, 31 of which were because of shock for >1 hour. Another weakness I found was that they did not report how they calculated the MAP and what percent had a-lines and what percent was calculated by non-invasively. This can be VERY important (See my post on MAP later). The final study randomized 155 patients to each group. The two groups looked otherwise pretty similar in their baseline characteristics. The intervention group was started on 0.5 mcg/kg/min fixed dose of epi and everyone was blinded to this intervention with a placebo in the control group. Time to getting norepi was pretty quick 93 minutes. Theoretically, you could say the norepi group could be differentiated by providers if they saw the BP go up. However, 20% of the normal saline placebo had an increase in the blood pressure. Both groups were allowed to have open label norepi The primary outcome here was time to shock control by measured MAP, urine output, and lactate. So, that is not the most fair primary outcome since obviously time to shock control will be faster in the norepi group. 76% of the norepi group vs 48% of the placebo group met the primary outcome. An interesting feature of the study was in the COMPOSITE primary outcome less than 10% of both groups reached the lactate clearance group whereas much more of the groups (35 vs 24) reached the urine output goal. This is more reason to make me wonder how useful lactate clearance is. A secondary outcome of mortality at 28 days, although NOT statistically significant was interestingly was a 6% difference (15.5 vs 21.9) in favor of the early norepi group. THIS METRIC IS DEFINITELY SOMETHING I’D LIKE TO SEE REPEATED IN A US STUDY AS THE PRIMARY OUTCOME. Another 5% mortality is impressive. 20% is what is typical of all the other sepsis trials (ARISE, PROMISE, etc.) with sick patients showed, so that would be impressive if early norepi could decrease this subsets mortality. The last interesting point is that there was no statistical difference in limb or organ ischemia between the two groups and half of the patients had only peripheral lines. These patients were in the hospital for a median of 10 days. It would be nice to know how long the patients had the norepi running. Also, many of these patients were admitted to the wards and NOT the ICU (about 50% of both groups). These two facts in addition to all the other literature on peripheral pressor’s really makes me feel better about running norepi peripherally. However that fact that this was based in a lower resource country with admissions criteria that are different also make it not as generalizable. So does this change practice? That waits to be seen, however, I have always felt that dumping in the magical 30ml/kg into a patient who is not hemorrhaging to be missing the point. I am biased toward giving early pressors…