Early administration of norepinephrine in sepsis: Multicenter randomized clinical trial (EA-NE-S-TUN) study protocol

Abstract

One of the most important components of sepsis management is hemodynamic restoration. If the target mean arterial pressure (MAP) is not obtained, the first recommendation is for volume expansion, and the second is for norepinephrine (NE). We describe the methodology of a randomized multicenter trial aiming to assess the hypothesis that low-dose NE given early in adult patients with sepsis will provide better control of shock within 6 hours from therapy starting compared to standard care. This trial includes ICU septic patients in whom MAP decrease below 65 mmHg to be randomized into 2 groups: early NE-group versus standard care-group. The patient's attending clinician will determine how much volume expansion is necessary to meet the target of a MAP > 65 mm Hg. If this target not achieved, after at least 30 ml/kg and guided by the available indices of fluid responsiveness, NE will be used in a usual way. The latter must follow a consensual schedule elaborated by the investigating centers. Parameters to be taken at inclusion and at H6 are: lactates, cardiac ultrasound parameters (stroke volume (SV), cardiac output (CO), E/E' ratio), and P/F ratio. MAP and diuresis are recorded hourly. Our primary outcome is the shock control defined as a composite criterion (MAP > 65 mm Hg for 2 consecutive measurements and urinary output > 0.5 ml/kg/h for 2 consecutive hours) within 6 hours. Secondary outcomes: Decrease in serum lactate> 10% from baseline within 6 hours, the received fluid volume within 6 hours, variation of CO and E/E', and 28 days-Mortality. The study is ongoing and aims to include at least 100 patients per arm. This study is likely to contribute to support the indication of early initiation of NE with the aim to restrict fluid intake in septic patients. (ClinicalTrials.gov ID: NCT05836272).

Fig 1. Spirit schedule of the study protocol.

Once sepsis with hypotension is diagnosed in and consent is obtained, he is eligible and according to randomization he is allocated either to the early NE or placebo group. Are recorded clinical and biological data (blood gases, lactate, ionogram and renal function), basic cardiac echocardiography (stroke volume (SV), cardiac output (CO) and E/E’ ratio in addition to standard care according to SSC 2021, measurement of MAP every 15 mn and hourly monitoring of urine flow until H6. At H6: in addition to the clinical parameters of interest (MAP and diuresis), lactate levels, echo cardiographic parameters and fluid received. Clinical monitoring will be carried out until discharge in order to determine Vasopressors free days, ICU stay, ventilator free days, and 28 days-Mortality.