Question: Given the recent studies showing the advantages of early norepinephrine in sepsis, should we titrate more aggressively to a higher MAP vs the standard 65-70?

Study 1:

• Single center, randomized, double-blind, placebo-controlled study of 310 patients with septic shock, to assess the efficacy of early norepinephrine administration in regard to shock control compared with standard care (30cc/kg fluid resuscitation)
• Primary endpoint was shock control at 6 hours after initiation as defined as MAP >= 65 mm Hg, urine flow >= 0.5ml/kg/h for 2 consecutive hours, or decreased serum lactate >= 10%
• Secondary outcome was mortality at 28 days 
• Pts were 18 y/o or older who presented to the ED with hypotension and infection as the suspected cause and met criteria for sepsis according to Surviving Sepsis Campaign
• Shock control in the early NE group was significantly higher (76.1%) vs other group (48.4%)
• 28 day mortality was not significantly different (15.5% in NE group vs 21.9% in standard group)
• Early NE group also had lower rate of cariogenic pulmonary edema (14.4% vs 27.7%) and new onset arrhythmia (11% vs 20%)

Study 2:

• Randomized, blinded, multicenter, open-label trial of 776 patients with septic shock, undergoing resuscitation for septic shock with a mean arterial pressure of either 80-85mmHg (high target group (HTG)) vs 65-70mmHg (low target group (LTG))
• Primary endpoint was mortality at day 28, secondarily mortality at 90 days
• Patients were 18 y/o, had confirmed septic shock that was refractory to fluid resuscitation, if they required vasopressors (NE or Epi), and if they were evaluated w/in 6 hours of initiation of vasopressors. 
• Randomly assigned to HTG vs LTG for the initial 5 days of the study, 388 each
• 28 days they compared mortality between the HTG (36.6%) and LTG (34%)
• 90 days they found no significant difference in HTG (43.7%) vs LTG (42.3%)

Conclusions:  

• Interesting to see comparison of 2 studies that, although similar, looked at different variations of similar treatment plans, with similar desired outcomes. 
• Study #2 went a step further from the findings of study #1, (i.e. “we now know early vasopressors increase MAP and yield better outcomes for pts , so would up-titrating those MAPs be beneficial to pts in septic shock?”)
• While study #1 had some flaws with it generalizability, several other studies have shown similar results
• Both studies use good parameters to measure “success”, although “mortality” decreased may not necessarily equal better outcomes for patients. 
• Both presents strong data that I aptly demonstrate the benefit of initiation of early vasopressors
• I will follow the recommendation in my practice with patients that appear to be in septic shock. 
• I will not automatically hang norepinephrine with fluids, but I will have a low threshold to start it early if I feel there is not an adequate and immediate response to fluid resuscitation.

Reference: 

Study 1:  Permpikul, Tongyoo, Viarasilpa, et al. Early use of norepinephrine in septic shock resuscitation. (CENSER) American Journal of Respiratory Critical Care. 2019;199(9):1097-1105

Study 2: Asfar P, et al. High vs low blood pressure target in patients with septic shock. NEJM. 2014;370(17): 1583-1593​