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Early Norepinephrine Has Potential for Septic Shock

Morgenstern, Justin MD

doi: 10.1097/01.EEM.0000559967.24287.c5
    norepinephrine, septic shock
    norepinephrine, septic shock:
    norepinephrine, septic shock

    Standard sepsis algorithms have suggested completing a fluid bolus before starting vasopressors in patients with septic shock, but multiple observational trials have shown an association between early vasopressor use and improved outcomes. (Resuscitation. 2004;62[2]:249; Crit Care. 2014;18[5]:532;

    CENSER was the first randomized controlled trial to examine this. (Am J Respir Crit Care Med. 2019 Feb 1. doi: 10.1164/rccm.201806-1034OC.) The researchers enrolled adults 18 and older with a mean arterial blood pressure lower than 65 mm Hg with infection as the suspected cause. Patients were excluded if they were in septic shock for more than one hour or had a stroke, an acute coronary syndrome, acute pulmonary edema, status asthmaticus, active arrhythmias, active GI hemorrhage, pregnancy, seizure, drug overdose, trauma, need for immediate surgery, or advanced staged cancer.

    Patients were given norepinephrine (0.05 mcg/kg/min or about 3.5 mcg/min for a 70 kg adult) without titration for 24 hours or placebo (D5W). Both groups received protocol-driven sepsis management according to the 2012 surviving sepsis campaign guidelines, including antibiotics, crystalloid bolus, and source control. Fluid therapy was at the discretion of the treating physician. Open label vasopressors were added in both groups if a MAP >65 was not achieved after a 30 mL/kg fluid bolus.

    The primary outcome was shock control by six hours, defined as a MAP >65 on two consecutive blood pressures 15 minutes apart plus adequate tissue perfusion, as evidenced by a urine output of 0.5 mL/kg/hr or a 10 percent decrease in lactate. The researchers included 310 patients.

    These were sick patients, with an APACHE-II score of 20, a mean arterial blood pressure of 56, and a lactate of 2.8. The groups looked similar at the outset of the trial, but the norepinephrine group ultimately looked much better (76.1% vs. 48.4%; odds ratio: 3.4; 95% CI: 2.09-5.53; P<0.001). Their target MAP was achieved in 3.5 hours compared with 4.75 hours with placebo. Shock control was achieved at 4.75 hours compared with six hours with placebo.

    Mortality was 15.5 percent with norepinephrine v. 21.9 percent with placebo (relative risk [RR]: 0.79, 95%CI: 0.53-1.11; P=0.15). There was less cardiogenic edema (14.4% vs 27.7%, p=0.004) and fewer new onset arrhythmias (11% vs 20%, p=0.03) in the norepinephrine group. All other adverse events, including gut and limb ischemia, were similar between the groups. Renal replacement therapy was required in 12 percent of the norepinephrine group and 14 percent of the placebo group (p=0.51).

    Strengths and Problems

    CENSER was an important trial. Current guidelines continue to emphasize relatively large volumes of crystalloid resuscitation before starting vasopressors, but fluids can cause harm. (Intensive Care Medicine. 2018;44[6]:925;; Anaesthesiol Intensive Ther. 2017;49[5]:323;

    Two observational trials demonstrated an association between early vasopressor use and improved outcomes, including improved mortality, but observational trials are inherently limited by their various intrinsic biases. (Resuscitation. 2004;62[2]:249;; Crit Care. 2014;18[5]:532;

    This trial had a number of strengths, including appropriate blinding and allocation concealment, the use of an intention-to-treat analysis, and complete follow-up of their patients. On the other hand, it was a single-center trial, and there were hints that practices are somewhat different in Thailand, potentially limiting external validity. The exclusions were also broad and might eliminate a large number of the patients I see with septic shock. Unblinding was likely because it is difficult to mask the jump in blood pressure when starting norepinephrine. They also used lactate clearance as a marker of shock resolution, but recent evidence showed this is not a great marker to guide sepsis resuscitation. (JAMA. 2019;321[7]:654; “Sepsis Update 2019.” Feb. 21, 2019;

    The biggest problem was that the primary outcome is not a patient-oriented outcome. Raising blood pressure is a monitor-oriented outcome that doesn't necessarily equate to patient-important outcomes. (Raising the blood pressure doesn't matter much if it comes at the expense of tissue perfusion.) They added markers of tissue perfusion, but it wasn't clear how important lactate clearance is. I can buy urine output as a reasonable surrogate, but at the end of the day, it doesn't matter at all to patients how much they are urinating in the ICU if it doesn't lead to better outcomes after they leave the ICU.

    In this case, patient-oriented outcomes might have been better. The mortality number certainly looked better, although the trial wasn't powered for mortality, and the result wasn't statistically significant. It is reassuring that there weren't any of the serious side effects we worry about with vasopressors, but the trial was too small to be sure about potential harms.

    One interesting note is that norepinephrine was run peripherally if a central line wasn't placed (which was the case in almost 60 percent of the cohort). One case of skin necrosis was found in each group, which is clearly not different. So we effectively have a small RCT of norepinephrine used through a peripheral IV to bolster the data we already had indicating that this is a relatively safe practice. (First10EM. May21, 2018;

    It is also interesting to note the destination of these patients. Only half were treated in the ICU despite being in septic shock and each potentially being on a vasopressor. The rest were sent to the ward. Criteria for ICU admission were endotracheal intubation, need for renal replacement therapy, or need for invasive hemodynamic monitoring. We could be overusing ICU resources in Western settings, but this is an important difference that could limit external validity.

    It isn't time to change sepsis protocols yet, but this was a promising trial. Early norepinephrine improved some disease-oriented outcomes in this RCT, and there were hints that this might result in important patient benefit. I will probably change my practice somewhat, reaching for norepinephrine a little earlier than I have been, but I will wait for the necessary large, multicenter RCT before suggesting this routinely.

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    Dr. Morgensternis a community emergency physician currently practicing at Taranaki Base Hospital in New Plymouth, New Zealand. His blog,, is dedicated to resuscitation and evidence-based medicine and encourages skepticism and a mindset of constant questioning, humility, and scientific reasoning in medicine. Follow him on Twitter@First10EM.

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