Early Administration of Norepinephrine in Sepsis (EA-NE-TUN)

Early Administration of Norepinephrine in Sepsis (Tunisian Multicenter Randomized Trial)

The management of septic states includes, in addition to the specific treatment (antimicrobials and eradication of the source), a restoration of the hemodynamic disorders and assistance of the failing organs. In general, the restoration of hemodynamic disorders begins first with volume expansion, followed by the use of Noepinephrine (NE) when the target mean arterial pressure (MAP) is not reached after optimizing the intravascular volume. Recently, several studies have supported the interest of early NE on MAP, cardiac output and mortality. It is therefore tempting to restrict fluid administration even in the initial phase of hemodynamic management of severe sepsis by starting NE earlier.

Study Overview

• Status: Recruiting
• Conditions: Sepsis, Severe
• Intervention / Treatment: Drug: Norepinephrine Bitartrate; Other: Placebo

Detailed Description

Sepsis is characterized by systemic inflammation induced by a severe infection resulting in an inappropriate host response against that infection. On the microcirculatory scale, vasoplegia with capillary leakage is distinguished. Management of sepsis includes, in addition to specific treatment which includes antimicrobials and eradication of the source, restoration of hemodynamic disorders and assistance to failing organs. In general, the restoration of hemodynamic disorders begins first with volume expansion, followed by the use of vasopressors (mainly norepinephrine: NE as first-line therapy) when the mean arterial pressure target (MAP: reflecting the perfusion pressure organs) is not reached after optimizing the intravascular volume.

Recently, several studies have supported the benefit of administering NE at the start of resuscitation of sepsis. Indeed, its administration at an earlier phase than usually recommended improved MAP and cardiac output with a favorable effect on mortality. At a median interval of 1.3 hours from ICU admission and exclusive administration of NE, MAP was adequately restored within a relatively short time (30 min) and was associated with a better survival rate than that predicted by the severity scores of similar patients from other series reported in the literature. In the recent Thai "CENSER" trial, shock was controlled in 76% of patients in the early NE group versus 48% (p<0.001). On the other hand, the administration of a large quantity of fluids inevitably increases the risk of fluid overload, which is a frequent complication in septic patients. In front of all these arguments, it is therefore tempting to restrict fluid administration even to the initial phase of the hemodynamic management of sepsis by starting NE earlier.

• Study Type: Interventional
• Enrollment (Estimated): 200
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Ahlem Trifi; Phone Number: 98692699; Email: trifiahlem2@gmail.com

Study Locations

• Tunisia
  • Tunis, Tunisia, 1007
    • Recruiting
    • intensive care unit of the University Hospital Center La Rabta
    • Contact: Ahlem Trifi; Phone Number: +21698692699; Email: ahlem.ahurabta@gmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age 18 or older.
• The patient or his/her legal representative has given informed consent in writing.
• Diagnosis of sepsis according to the definitions updated by the consensus of sepsis 3.
• Mean arterial pressure < 65 mmHg

Exclusion Criteria:

• Diagnosis of septic shock prior to randomization (where NA requirements exceed those of the trial protocol)
• Pregnancy,
• Need for immediate surgery,
• Neoplasia at an advanced stage
• Circumstances where water restriction is the rule:
• Acute pulmonary edema
• Acute coronary syndrome,

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Early NE; The early NE arm will receive low-dose NE as soon as hypotension secondary to sepsis is observed in addition to a classic therapeutic regimen that complies with the guidelines of the 2021 Surviving Sepsis Compaign. Sepsis is defined according to the sepsis 3 consensus by a sepsis related organ failure assessment (SrOFA) score greater than 2 following an infection (documented or suspected)	Drug: Norepinephrine Bitartrate; The NE will be prepared as follows: 4 mg mixed with 250 ml of 5% glucose resulting in a final norepinephrine concentration of 0.016 mg/ml. For the control group placebo: 250 ml of 5% glucose will be prepared. Both drugs will be infused via a peripheral line or a venous catheter. The intravenous infusion rate varies from 8 to 15 ml/hour, adjusted according to body weight to obtain norepinephrine at 0.05 microgram/kg/min (ie 0.128 to 0.24 mg per hour) in continuous infusion.; Other Names: Norepinephrine 0,016 mg/ml
Placebo Comparator: Placebo; The placebo arm will receive only the classic therapeutic regimen that complies with the guidelines of the 2021 Surviving Sepsis Compaign.	Other: Placebo; For the control group placebo: 250 ml of 5% glucose will be prepared and will be infused via a peripheral line or a venous catheter. The intravenous infusion rate varies from 8 to 15 ml/hour.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
shock control	shock control is defined by 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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mortality	Mortality	28 days
Decrease in serum lactate	Decrease in serum lactate > 10% from baseline	within 6 hours
Volume of fluid	Quantity of intravenous fluid received	within 48 hours

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Use of invasive ventilation	Use of invasive ventilation	48 hours
Variation of cardiac output	Variation of Cardiac output assessed xith transthoracic cardiac ultrasound (the 15% threshold is considered to define an increase in CO).	Within 6 hours

Collaborators and Investigators

• Sponsor: Tunis University
• Investigators: Principal Investigator: Ahlem Trifi, Hopital La Rabta

Publications and helpful links

General Publications

• 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. doi: 10.1164/rccm.201806-1034OC.

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2023
• Primary Completion (Estimated): June 1, 2025
• Study Completion (Estimated): August 1, 2025

Study Registration Dates

• First Submitted: April 18, 2023
• First Submitted That Met QC Criteria: April 18, 2023
• First Posted (Actual): May 1, 2023

Study Record Updates

• Last Update Posted (Estimated): December 4, 2024
• Last Update Submitted That Met QC Criteria: December 2, 2024
• Last Verified: December 1, 2024

More Information

Terms related to this study

• Keywords: septic shock; sepsis; mortality; Norepinephrine; volume expansion
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Sepsis; Toxemia; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Neurotransmitter Agents; Adrenergic alpha-Agonists; Adrenergic Agonists; Adrenergic Agents; Sympathomimetics; Vasoconstrictor Agents; Norepinephrine
• Other Study ID Numbers: Tunisian ICUs association

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No