Early Administration of Norepinephrine in Sepsis

NCT ID: NCT05836272

Last Updated: 2024-12-04

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE4
• Total Enrollment: 200 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2023-08-01
• Study Completion Date: 2025-08-31

Brief Summary

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.

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.

Conditions

Sepsis, Severe

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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)

Group Type: ACTIVE_COMPARATOR

Norepinephrine Bitartrate

Intervention Type: DRUG

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.

Placebo

The placebo arm will receive only the classic therapeutic regimen that complies with the guidelines of the 2021 Surviving Sepsis Compaign.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: OTHER

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.

Interventions

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.

Intervention Type: DRUG

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.

Intervention Type: OTHER

Other Intervention Names

Norepinephrine 0,016 mg/ml

Eligibility Criteria

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,

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Tunis University

OTHER

Sponsor Role: lead

Responsible Party

Ahlem Trifi

Associate Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Ahlem Trifi

Role: PRINCIPAL_INVESTIGATOR

Hopital La Rabta

Locations

intensive care unit of the University Hospital Center La Rabta

Tunis, , Tunisia

Site Status: RECRUITING

Countries

Tunisia

Central Contacts

Ahlem Trifi

Role: CONTACT

trifiahlem2@gmail.com

98692699

Facility Contacts

Ahlem Trifi

Role: primary

ahlem.ahurabta@gmail.com

+21698692699

References

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.

Reference Type: BACKGROUND

PMID: 30704260 (View on PubMed)

Trifi A, Abdellatif S, Mehdi A, Messaoud L, Seghir E, Mrad N, Ben Khelil J, Ben Ismail K, Merhaben T, Fradj H, Mokline A, Messaadi AA, Khiari H, Garbaa Y, Borsali Falfoul N, Ennouri E, Toumi R, Boussarsar M, Jaoued O, Atrous S, Ghezala HB, Brahmi N, Trabelsi I, Ghadhoune H, Bradaii S, Bahloul M, Ammar R, Kaaniche FM. Early administration of norepinephrine in sepsis: Multicenter randomized clinical trial (EA-NE-S-TUN) study protocol. PLoS One. 2024 Jul 18;19(7):e0307407. doi: 10.1371/journal.pone.0307407. eCollection 2024.

Reference Type: DERIVED

PMID: 39024364 (View on PubMed)

Other Identifiers

Tunisian ICUs association

Identifier Type: -

Identifier Source: org_study_id