Early Norepinephrine Administration in Septic Shock

July 2019



You are working an overnight shift in TCC one evening when you get the following page: “Triage patient to 3L.”  No other information is provided, but when the patient finally appears you find that she is a fifty-eight year female wiht a history of rheumatoid arthritis treated with methotrexate infusions.  She is coming in now wiht one week of increasing cough, productive of green sputum, fevers, chills, and shortness of breath.  Her initial triage vital signs are as follows:

HR 124 BP 82/40          SpO2 89% (ORA)          T 38.8          RR 21

Her physical exam reveals a well-nourished female with mild tachypnea, uncomfortable appearing but in no distress.  She has no cardiac murmur, rub, or gallop, but on lung auscultation has rhonchi in the left lung base.  Her abdomen is soft, nondistended, and nontender, and she has no lower extremity edema.  Her skin is cool and dry.

For her hypoxia, she is placed on 2 liters of oxygen by  nasal cannula.  A peripheral IV is placed, blood cultures and labs are drawn, and a chest x-ray is ordered.  Recognizing that the patient meets criteria for sepsis and is hypotensive.  You know that the patient requires aggressive resuscitation with 30mL/kg of isotonic fluid, but while ordering this, you wonder if you should also initiate vasopressors.  while your attending instructs you to wait and see how she responds to the fluid bolus, you remember reading an article in one of the “throw away” journals you receive suggesting that there was a benefit to early norepinephrine administration in sepsis, initiated concomitant with fluid resuscitation.

After the patient’s fluid bolus, she remains hypotensive (MAP 59) and a norepinephrine is initiated.  As the patient is transported to hte MICU, you begin to wonder what evidence there is looking at early norepinephrine administration in patients with sepsis and hypotension.  After your shift, you go home and do your own literature search…..

PICO Question

Population: Adult patients septic shock, defined as the presence of two or more SIRS criteria plus an infectious source plus a mean arterial pressure (MAP) <65

Intervention: Early norepinephrine drip, initiated prior to completion of fluid resuscitation

Comparison: Standard of care (typically initiation of norepinephrine when MAP <65 mmHg following adequate fluid resuscitation)

Outcome: Mortality, resolution of shock, ICU/hospital length of stay, duration of antibiotic administration, need for mechanical ventilation, need for renal replacement therapy

Search Strategy

The recently published CENSER trial was chosen given its recent publicity and potential for high impact.  Three additional articles were chosen from the references in this paper.  PubMED was searched using the terms “early AND norepinephrine AND sepsis” (https://tinyurl.com/y4tx43ls), but this did not identify any additional,
more relevant studies.


Article 1: Bai X, Yu W, Ji W, Lin Z, Tan S, Duan K, Dong Y, Xu L, Li N. Early versus
delayed administration of norepinephrine in patients with septic shock. Crit Care. 2014
Oct 3;18(5):532. ANSWER KEY

Article 2: Permpikul C, Tongyoo S, Viarasilpa T, Trainarongsakul T, Chakorn T,
Udompanturak S. Early Use of Norepinephrine in Septic Shock Resuscitation
(CENSER). A Randomized Trial. Am J Respir Crit Care Med. 2019 May 1;199(9):
1097-1105. ANSWER KEY

Article 3: Morimatsu H, Singh K, Uchino S, Bellomo R, Hart G. Early and exclusive use of norepinephrine in septic shock. Resuscitation. 2004 Aug;62(2):249-54.

Article 4: Hamzaoui O, Georger JF, Monnet X, Ksouri H, Maizel J, Richard C, Teboul
JL. Early administration of norepinephrine increases cardiac preload and cardiac output
in septic patients with life-threatening hypotension. Crit Care. 2010;14(4):R142.

Bottom Line

The management of sepsis and septic shock has undergone major shifts over the last two decades, including the introduction of early goal-directed therapy and the emergency of norepinephrine as first-line vasopressor for the treatment of refractory hypotension.  While studies published in the last five years have called into question certain tenets of early goal-directed therapy, including use of central venous oxygen saturation and routine measurement of central venous pressure, the basics of resuscitation in septic shock have largely remained unchanged.

One question that has arisen in more recent years has been the timing of initiation of norepinephrine in hypotensive patients.  Protocols have typically involved an initial fluid bolus (typically 20 to 30 mL/kg of isotonic crystalloid) followed by use of norepinephrine in patients with persistent hypotension. The recently published CENSER trial has called this sequence into question, suggesting that a norepinephrine infusion should eb instituted prior to completion of the fluid bolus in patients with septic shock.  In addition to providing vasoconstrictive effects to improve the blood pressure, at least one observational study (Hamzaoui 2010) has also demonstrated improved cardiac output, global end-diastolic volume index, and cardiac function index among patients with sepsis treated with a norepinephrine drip.

Prior to the release of the CENSER trial, there was limited data regarding the early administration of norepinephrine in septic shock.  Two previous retrospective, observational studies have looked at early use of norepinephrine.  The the first of these (Morimatsu 2004), use of norepinephrine “irrespective of fluid resuscitation” resulted in lower mortality than predicted by SAPS II score, particularly among those at higher risk of death.  Unfortunately, this study did not have an actual control group, and any comparison to predicted mortality is purely theoretical.  In addition, the study was conducted entirely in the ICU rather than the emergency department (external validity).  A subsequent study (Bai 201), also conducted solely in the ICU, compared early norepinephrine administration (less than two hours from the onset of shock) to late administration (two or more hours from onset of septic shock) and found that those who got norepinephrine early had lower 28-day mortality (OR 1.86%, 95% CI 1.04 to 3.34).  For every hour delay in initiation of a norepinephrine infusion, the OR for death was 1.20 (95% CI 1.07 to 1.35), correspnonding to a 20.4% increase in the risk of death.  Again, this study was limited by its location in a surgical ICY, as well as by its retrospective, observational nature.

The CENSER trial (Permpikul 2019), published earlier this year, was a blinded, randomized controlled trial conducted in the emergency department of a single center in Bangkok, Thailand between 2013 and 2017.  Adults with sepsis and a MAP (65 mmHg were randomized to either placebo or a low-dose norepinephrine infusion at the time of enrollment, with all other care at the descretion of the treating clinicians, including titratable norepinephrine if deemed necessary.  The results demonstrated a higher rate of shock control (sustained MAP ≥ 65 with evidence of adequate tissue perfusion) at 6 hours among patients receiving the norepinephrine drip. There was additionally a trend toward decreased 28-day mortality, but this did not achieve statistical significance (RR 0.79, 95% CI 0.53 to 1.11).

Unfortunately, these data are, overall, quite limited. CENSER is the only randomized trial to date to compare early norepinephrine infusion to delayed infusion following fluid
resuscitation in the emergency department. While this study demonstrated improvement in a surrogate outcome (shock control at 6 hours) it failed to demonstrate an improvement in any patient-centered outcomes. Despite this lack of concrete data, it seems reasonable to start a norepinephrine infusion prior completion of fluid resuscitation in hypotensive patients with sepsis, particularly in those with more severe hypotension (i.e. MAP < 40).