Evaluation of Early Association of Terlipressin and Norepinephrine During Septic Shock; the TerliNor Study

Study Overview
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Brief Summary
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In guidelines norepinephrine is the first line vasopressor recommended in case of septic shock. Use of vasopressin is recommended when norepinephrine fails to maintain a mean arterial pressure above 65mmHg or in salvage. Several studies failed to show a superiority of vasopressin over norepinephrine but none evaluated the effect of an early association on organ failure. Terlipressin is a pro-drug of vasopressin which has the same vasoconstrictor effect. We hypothesize that the early association of terlipressin and norepinephrine during septic shock reduces organ failure. This bi centric, double-blinded, randomised, controlled versus placebo study includes 40 patients. Randomisation will be stratified between centers (two university affiliated intensive care units of Assistance-Publique-Hôpitaux de Marseille, Marseille, France). All patients with septic shock needing more than 0,5µg/kg/min of norepinephrine to reach PAM objectives are randomised, after hemodynamic evaluation and optimisation, to receive continuous infusions of terlipressin (0,01mg/kg/min) or placebo (physiologic serum). The 2 groups receive steroid therapy (continuous intravenous hydrocortisone perfusion) at this time. Clinicians are blinded of perfusion used. Use of terlipressin remains possible in salvage when patients need more of 1µg/kg/min of norepinephrine on physician's decision. Patients with acute ischemic or septic heart failure are excluded of the study. Primary objective is sepsis related Sequential Organ Failure Assessment (SOFA) score difference between the groups at day 3. Secondary objectives are mortality at day 28, lactates clearance in the first 48hours, renal function (evaluates with AKIN criteria) and use of renal replacement therapy.

Official Title
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Evaluation of Early Association of Terlipressin and Norepinephrine During Septic Shock; the TerliNor Study

Conditions
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Septic Shock

Intervention / Treatment
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* Drug: Terlipressin
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Older than 18 years Dose of norepinephrine greater than 0.3 μg / kg / min Lactate greater than 2.0 mmol / l Exclusion Criteria: A left heart failure objectified in ultrasound transthoracique by a fraction of left(awkward) ejection of the ventricle lower than 30 % either by thermodilution transpulmonaire with a cardiac index lower than 2,5 l / min / m2 after optimization of the volémie or a central venous saturation in oxygen ( SVcO2) lower than 60 % after optimization of the blood volume. Minors Pregnant Not having terlipressin allergy Not having excipient allergy A history known for recent acute coronary syndrome (< 3mois) An acute coronary syndrome defined by an increase of the troponine and a rise of the segment ST in the electrocardiogram

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: terlipressin associated with norepinephrine<br> | Drug: Terlipressin<br>* Administration of terlipressine<br>|
| Placebo Comparator: placebo (physiologic serum) associated with norepinephrine<br> | Other: Placebo<br>* Administration of placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sequential Organ Failure Assessment (SOFA) score difference between the groups |  | Day 3 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mortality rate |  | Day 28 | 
| Lactates clearance |  | 48 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Terlipressin, norepinephrine