Evaluation of the Effect of Dexmedetomidine on Phenylephrine Response During Refractory Septic Shock

NCT03953677 | Terminated Phase 3

• 1 other identifier: DARGENT APJ 2018
• Study Type: interventional
• Target: 32
• Locations: 1 country
• Sites: 1

Brief Summary

Septic shock is common in patients admitted to intensive care and hospital mortality occurs in close to 50% of these patients. In half of the cases, death occurs within the first 72 hours in a context of multiple organ failure that does not respond to conventional therapies, particularly circulatory therapies, despite increasing doses of catecholamines. Vasopressor resistance in septic patients defines refractory septic shock. In one study (Conrad et al. 2015), the increase in blood pressure observed with an infusion of increasing doses of phenylephrine (dose-response curve) made it possible to quickly and clearly identify patients resistant to vasopressors at a high risk of death by refractory shock (ROC AUC 0.92). This resistance is due in particular to a downregulation of α1 adrenergic receptors, linked to sympathetic hyper activation associated with septic shock. To date, there is no validated therapy in this situation. However, experimental data have shown that the administration of α2 agonists, usually used for their sedative (dexmedetomidine) or anti-hypertensive (clonidine) effect, normalizes sympathetic activity towards basal values. In animals, α2 agonists restore the sensitivity of alpha1 adrenergic receptors, resulting in improved vasopressor sensitivity and survival. In humans, a beneficial effect on mortality was suggested in the first trial testing dexmedetomidine in septic patients in 2017. This effect was observed especially in the most severe patients, suggesting a restoration of sensitivity to vasopressors. The hypothesis is that the administration of dexmedetomidine in patients in refractory septic shock may improve response to phenylephrine and decrease resistance to vasopressors. This pilot study could lay the foundation for a randomized controlled trial.

Conditions

Septic Shock; Vasopressor Resistance

Outcome Measures

Primary Outcomes (1)

• Relative change in mean blood pressure, expressed as a percentage

  Relative variation in mean blood pressure between the basal value at the beginning of the test and the value reached at the dose of 6 µg/kg/min (%PAM0 = PAMd/PAM0 x100)

  6 hours after the end of the initial test

Study Arms (2)

Dexmedetomidine

EXPERIMENTAL

Drug: Dexmedetomidine 100 Mcg/mL Intravenous Solution

Placebo

PLACEBO COMPARATOR

Drug: 5% glucose Infusion solution

Interventions

Dexmedetomidine 100 Mcg/mL Intravenous Solution DRUG

Continuous infusion of dexmedetomidine at 0.7 µg/kg/h for 2 hours and then 1 µg/kg/h at fixed dose

Dexmedetomidine

5% glucose Infusion solution DRUG

Continuous infusion of placebo (5% glucose) at 0.7 µg/kg/h for 2 hours and then 1 µg/kg/h at fixed dose

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age ≥ 18 years old
• Septic shock, defined by the "Sepsis-3" criteria
• proven or suspected infection, with modification of the SOFA score ≥ 2 points,
• with persistent hypotension requiring vasopressors to maintain MAP ≥ 65 mmHg
• and a serum lactate level \> 2 mmol/L despite adequate vascular filling
• Adequate vascular filling: ≥ 30ml/kg, OR absence of preload-dependency criteria at time of assessment (respiratory variability of the inferior vena cava, passive leg lift, pulsed pressure variation)
• Catecholamine resistance, defined by the need for a dose of norepinephrine ≥ 0,5 µg/kg/min for more than 2 consecutive hours within 24 hours of admission to intensive care unit
• persistence of circulatory failure with at least one of the following criteria present in the 2 hours prior to randomisation: hyperlactatemia \> 2mmol/l, and/or mottling (≥ 1 score), and/or oliguria (diuresis \< 0,5 ml/kg/h over the last 2 hours)
• Invasive Mechanical ventilation
• Under sedation by midazolam or propofol
• Informed consent obtained from a relative for patient included in an emergency
• Patient affiliated to the national health insurance system

You may not qualify if:

• Cardiac index \< 2.2 l/min/m² after volume correction, or left ventricular ejection fraction \< 40% on echocardiography
• Bradycardia \< 55 bpm (apart from treatment with β-blocker) or 2nd or 3rd degree BAV not equipped
• Proven or suspected decompensation of coronary heart disease
• Severe hepatic insufficiency with TP and factor V \<50% in the absence of DIC (disseminated intravascular coagulation)
• Patient for whom a decision has been made to limit the use of therapies
• Hypersensitivity to dexmedetomidine or phenylephrine
• Person subject to a legal protection measure (curatorship, guardianship)
• Person subject to limited judicial protection
• Pregnant, parturient or breastfeeding woman
• Patient with suspected or confirmed mesenteric ischemia

Sponsors & Collaborators

• Centre Hospitalier Universitaire Dijon: lead

Study Sites (1)

Chu Dijon Bourgogne

Dijon, 21000, France

Location

Related Publications (2)

• Dargent A, Bourredjem A, Jacquier M, Bohe J, Argaud L, Levy B, Fournel I, Cransac A, Badie J, Quintin L, Quenot JP. Dexmedetomidine to Reduce Vasopressor Resistance in Refractory Septic Shock: alpha2 Agonist Dexmedetomidine for REfractory Septic Shock (ADRESS): A Double-Blind Randomized Controlled Pilot Trial. Crit Care Med. 2025 Apr 1;53(4):e884-e896. doi: 10.1097/CCM.0000000000006608. Epub 2025 Feb 28.

  PMID: 40019329 RESULT

• Dargent A, Bourredjem A, Argaud L, Levy B, Fournel I, Cransac A, Badie J, Quintin L, Quenot JP. Dexmedetomidine to reduce vasopressor resistance in refractory septic shock: Protocol for a double-blind randomized controlled pilot trial (ADRESS Pilot study). Front Med (Lausanne). 2022 Aug 9;9:968274. doi: 10.3389/fmed.2022.968274. eCollection 2022.

  PMID: 36017005 DERIVED

MeSH Terms

Conditions

Shock, Septic

Interventions

Dexmedetomidine

Condition Hierarchy (Ancestors)

Sepsis; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Shock

Intervention Hierarchy (Ancestors)

Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 15, 2019
• First Posted: May 16, 2019
• Study Start: October 27, 2019
• Primary Completion: January 31, 2023
• Study Completion: March 22, 2023
• Last Updated: February 4, 2026

Record last verified: 2026-02

Locations

FR (1)