Efficacy of the Alpha 2 Agonist Dexmedetomidine for Sympathetic Deactivation in REfractory Septic Shock (ADRESS)

Efficacy of the Alpha 2 Agonist Dexmedetomidine for Sympathetic Deactivation in REfractory Septic Shock: a Randomized, Controlled Trial

Septic shock is one of the most frequent reasons for admission to intensive care units and remains associated with a high mortality rate of approximatively 40% at 28 days. Nearly half of deaths attributable to septic shock occur within the first 3 days and are directly related to the consequences of circulatory failure leading to multiple organ dysfunction. In some patients, persistent shock despite adequate resuscitation leads to early death. This condition is referred to as refractory septic shock. Although its pathophysiology if multifactorial, refractory septic shock is largely characterized by profound vasoplegia and reduced responsiveness to vasopressor therapy.

Current guidelines recommend norepinephrine as the first-line vasopressor. Vasopressin may be considered as a second-line agent, although the addition of vasopressin to norepinephrine has not consistently demonstrated a survival benefit compared with norepinephrine alone. Corticosteroids are also recommended in patients with refractory septic shock with a low level of evidence. Similarly, the addition of other vasopressors such as selepressin or angiotensin II may reduce catecholamine requirements but has not consistently demonstrated an improvement in mortality.

More recently, a meta-analysis evaluating all non-adrenergic therapeutic strategies confirmed that none of these strategies individually provides a clear mortally benefit. However, when considered collectively, non-adrenergic approaches were associated with improved outcomes in patients with septic shock, supporting the concept that strategies aimed at bypassing or limiting excessive catecholaminergic stimulation may be beneficial in this population.

In parallel, α2-adrenergic agonists are increasingly used as sedative agents in intensive care. Dexmedetomidine has been shown in experimental models to restore vascular responsiveness to vasopressors. Clinical studies conducted in patients with severe sepsis or septic shock have also suggested a potential benefit, including reduced vasopressor requirements and improved hemodynamic stability in the most severely ill patients. Therefore, dexmedetomidine may provide clinically relevant benefits through improved hemodynamic control during the acute phase of septic shock. By restoring vasopressor sensitivity, dexmedetomidine could potentially address an important therapeutic gap in the management of refractory septic shock.

The underlying hypothesis is that the downregulation of adrenergic receptors observed during sepsis may be a direct consequence of sympathetic hyperactivation. Reversal of this phenomenon through "sympathetic deactivation" using α2-agonists may restore vascular responsiveness to vasopressors.

To prepare the ADRESS trial, the investigator's team conducted a multicenter, randomized, double-blind pilot study (ADRESS Pilot). The primary objective of ADRESS Pilot was to assess the effect of dexmedetomidine on vascular responsiveness to phenylephrine in patients with septic shock and vasopressor resistance. Mortality was also evaluated as a secondary outcome. Thirty-two patients were randomized (16 per group). Due to the small sample size, an imbalance in baseline characteristics was observed, with greater vasopressor resistance in the dexmedetomidine group at the time of randomization, even before treatment administration. Patients allocated to the dexmedetomidine group had lower baseline responsiveness to phenylephrine, which limited the comparability of the groups and made the interpretation of the results particularly challenging.

Nevertheless, 30-day and 90-day mortality were not significantly higher in the dexmedetomidine group. No significant differences were observed between groups in the occurrence of bradycardia or in heart rate. Several sensitivity analyses adjusting for baseline imbalances did not demonstrate a clear beneficial effect of dexmedetomidine. However, these findings may reflect insufficient statistical power, given the very small sample size of the study.

Therefore, a larger and adequately powered trial is required to determine whether dexmedetomidine provides a clinical benefit in patients with refractory septic shock.

Based on the results of ADRESS Pilot, the investigator propose to adapt the design of the ADRESS trial to increase the likelihood of detecting a potential treatment effect. Following the pilot study, the scientific committee decided to modify the study design from a double-blind to an open-label trial in order to reduce the risk of excessive sedation resulting from the addition of a sedative drug in patients already receiving continuous sedation. The target population consists of patients with refractory septic shock and a high risk of mortality. These patients are likely to derive the greatest benefit from a sympathetic deactivation strategy using dexmedetomidine in order to improve clinical outcomes.

Study Overview

• Status: Not yet recruiting
• Conditions: Septic Shock, Vasopressor Resistance
• Intervention / Treatment: Drug: Dexmedetomidine 100 µg/mL, intravenous solution; Other: Stardard care

• Study Type: Interventional
• Enrollment (Estimated): 360
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Auguste DARGENT, Doctor; Phone Number: +33 4 78 86 20 06; Email: auguste.dargent@chu-lyon.fr
• Study Contact Backup: Name: Jean-Pierre QUENOT, Professor; Phone Number: +33 3 80 29 37 51; Email: jean-pierre.quenot@chu-dijon.fr

Study Locations

• France
  • Amiens, France, 80054
    • CHU Amiens-Picardie - Service de médecine intensive-réanimation
    • Contact: Yoann ZERBIB, MD; Phone Number: +33322088000; Email: zerbib.yoann@chu-amiens.fr
    • Principal Investigator: Yoann ZERBIB, MD
  • Chalon-sur-Saône, France, 71321
    • Centre Hospitalier Chalon-sur-Saône - Service de réanimation et surveillance continue
    • Principal Investigator: Thomas MALDINEY, MD
    • Contact: Thomas MALDINEY, MD; Phone Number: +333 85 91 01 11; Email: thomas.maldiney@ch-chalon71.fr
  • Dieppe, France, 76202
    • Centre Hospitalier de Dieppe - Service de réanimation et unité de soins continus
    • Contact: Antoine MARCHALOT, MD; Phone Number: +33232147253; Email: AMarchalot@ch-dieppe.fr
    • Principal Investigator: Antoine MARCHALOT, MD
  • Dijon, France, 21000
    • CHU Dijon Bourgogne - Service de médecine intensive et réanimation
    • Principal Investigator: Jean-Pierre QUENOT, MD
    • Contact: Jean-Pierre QUENOT, MD; Phone Number: +33380293751; Email: jean-pierre.quenot@chu-dijon.fr
  • Garches, France, 92380
    • APHP - Hôpital Raymond-Poincaré - Service de Médecine intensive-réanimation
    • Principal Investigator: Djillali ANNANE, MD
    • Contact: Djillali ANNANE, MD; Phone Number: +331 47 10 77 78; Email: djillali.annane@aphp.fr
  • La Roche-sur-Yon, France, 85925
    • Centre Hospitalier Départemental de Vendée - Service de réanimation polyvalente
    • Contact: Samuel GENSBURGER, MD; Phone Number: +332 51 44 61 61; Email: samuel.gensburger@ght85.fr
    • Principal Investigator: Samuel GENSBURGER, MD
  • Le Mans, France, 72037
    • Centre Hospitalier Le Mans - Service de réanimation médico-chirurgicale
    • Principal Investigator: Jean-Christophe CALLAHAN, MD
    • Contact: Jean-Christophe CALLAHAN, MD; Phone Number: +332 43 43 24 58; Email: jccallahan@ch-lemans.fr
  • Lyon, France, 69003
    • Hôpital Edouard Herriot - Service de Médecine intensive - reanimation
    • Principal Investigator: Laurent ARGAUD, MD
    • Contact: Laurent ARGAUD, MD; Phone Number: +334 72 11 28 62; Email: laurent.argaud@chu-lyon.fr
  • Lyon, France, 69004
    • Hôpital de la Croix Rousse - Service de médecine intensive et réanimation
    • Principal Investigator: Louis CHAUVELOT, MD
    • Contact: Louis CHAUVELOT, MD; Phone Number: +33472071762; Email: louis.chauvelot@chu-lyon.fr
  • Lyon, France, 69007
    • Hôpital Saint Joseph Saint Luc - Service de réanimation
    • Principal Investigator: Emmanuel VIVIER, MD
    • Contact: Emmanuel VIVIER, MD; Phone Number: +334 78 61 88 18; Email: evivier@saintjosephsaintluc.fr
  • Nice, France, 06200
    • Hôpital de l'archet - Service de médecine intensive et réanimation
    • Contact: Alan MOUROUGAYEN, MD; Phone Number: +334 92 03 77 77; Email: mourougayen.a@chu-nice.fr
    • Principal Investigator: Alan MOUROUGAYEN, MD
  • Pierre-Bénite, France, 69310
    • Service d'Anesthésie - Médecine Intensive - Réanimation Hôpital Lyon Sud
    • Contact: Auguste DARGENT, Doctor; Phone Number: +33 4 78 86 20 06; Email: auguste.dargent@chu-lyon.fr
    • Principal Investigator: Auguste DARGENT, MD
  • Rennes, France, 35033
    • CHU de Rennes - Service de médecine intensive et réanimation
    • Principal Investigator: Nicolas TERZI, MD
    • Contact: Nicolas TERZI, MD; Phone Number: +33299284321; Email: Nicolas.TERZI@chu-rennes.fr
  • Saint-Priest-en-Jarez, France, 42270
    • Hôpital Nord - CHU Saint Etienne - Service de médecine intensive
    • Contact: Sophie PERINEL, MD; Phone Number: +33477828002; Email: sophie.perinel.ragey@univ-st-etienne.fr
    • Principal Investigator: Sophie PERINEL, MD
  • Strasbourg, France, 67091
    • Nouvel Hôpital Civil - Service de médecine intensive et réanimation
    • Contact: Julie HELMS, Professor; Phone Number: +333 69 55 04 34; Email: julie.helm@chru-strasbourg.fr
    • Principal Investigator: Julie HELMS, Professor
  • Toulon, France, 83100
    • Centre Hospitalier Intercommunal de Toulon - Service de réanimation polyvalente
    • Principal Investigator: Jonathan CHELLY, MD
    • Contact: Jonathan CHELLY, MD; Phone Number: +334 94 14 50 00; Email: jonathan.chelly@ch-toulon.fr
  • Trévenans, France, 90400
    • HOPITAL NORD FRANCHE-COMTE - Service de réanimation
    • Contact: Paul MONASTEROLO, MD; Phone Number: +333 84 98 21 91; Email: PAUL.MONASTEROLO@hnfc.fr
    • Principal Investigator: Paul MONASTEROLO, MD
  • Villeurbanne, France, 69100
    • Médipôle Hôpital Privé Lyon Villeurbanne- Service de réanimation polyvalente
    • Contact: Stanislas LEDOCHOWSKI, MD; Phone Number: +334 87 65 01 88; Email: sledochowski@scprea.fr
    • Principal Investigator: Stanislas LEDOCHOWSKI, MD

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Age ≥ 18 years old
• Septic shock, defined by the "sepsis-3" criteria :

oProven or suspected infection, with modification of the SOFA score ≥ 2 points oWith persistent hypotension requiring vasopressors to maintain MAP ≥ 65 mmHg

• And serum lactate level > 2 mmol/L despite adequate vascular filling

  - Catecholamine resistance, defined by

• The need for a dose of norepinephrine ≥ 0.5 µg/kg/min for more than 2 consecutive hours

• AND persistence of circulatory failure with at least one of the following criteria present in the 2 hours prior to randomization : hyperlactatemia (> 2 mmol/L) and/or mottling (score ≥ 1) and/or oliguria (diuresis < 0.5 mL/kg/h over the last 2 hours)

  • Adequate vascular filling : ≥ 30 mL/kg OR absence of preload-dependency criteria at time of assessment (passive leg lift, pulsed pressure variation)
  • Invasive mechanical ventilation
  • Patient affiliated to the national heatlh insurance system
  • Written consent from the

Exclusion Criteria:

• Cardiac index < 2.2 L/min/m2 after volume correction
• Bradycardia < 55 bpm (apart from treatment with ẞ-bloquant) or 2nd or 3rd degree BAV not equipped
• Patients who are moribund or for whom death appears imminent within 24 hours (as determined by the investigator's clinical judgment
• Severe hepatic insufficiency with TP and factor < 50% in the absence of DIC (disseminated intravascular coagulationà
• Hypersensitivity to dexmedetomidine
• Patient on dexmedetomidine before inclusion
• Patients who received iproniazide within the 15 days preceding randomization
• Patient for whom a decision has been made to limit the use of therapies
• Person subject to limited judicial protection or a legal protection measure (curatorship, guardianship)
• Patients participating in another clinical study with an ongoing exclusion period at the time of inclusion
• Pregant or breastfeeding woman

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
Experimental: Dexmedetomidine 100 µg/Ml; Patients in the experimental arm will receive a continuous infusion on dexmedetomidine at 0.7 µg/kg/h for the first 2 hours, and then 1 µg/kg/h at fixed dosed, as long as sedation and/or a norepinephrine dose >0.1 µg/kg/min is required, for a maximum duration of 14 days. The dose will be halved 2 hours prior to complete weaning.	Drug: Dexmedetomidine 100 µg/mL, intravenous solution; Continuous infusion on dexmedetomidine at 0,7 μg/kg/h for 2 hours and then 1 μg/kg/h at fixed dose
Other: Standard care; Patients in the standard care arm will receive optimized, protocolized management in strict adherence to current guidelines, particularly regarding fluid administration, source control, antibiotic therapy, and substitutive corticosteroid therapy	Other: Stardard care; fluid administration, source control, antibiotic therapy, and substitutive corticosteroid therapy in strict adherence to current guidelines

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
30-day mortality	Vital status at day 30 after randomization.	Day 30 after randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
72-hour mortality	Vital status at 72 hours after randomization	72 hours after randomization
Vasopressor exposure	Cumulative vasopressor dose and peak vasopressor dose expressed as norepinephrine-equivalent dose (NEE score)	6, 12 and 24 hours after randomization
Use of vasopressin or recue therapies	Proportion of patients requiring vasopressin or any therapy for refractory shock during follow-up	From randomization to day 30
Mean arterial pressure (MAP)	Evolution of mean arterial pressure (MAP) and MAP to norepinephrine-equivalent (Neq) dose ration (MAP/Neq) to assess vasopressor responsiveness	Baseline, 6 hours, 12 hours and 24 hours after randomization
Vasopressor-free days	Number of days without vasopressor therapy during the first 30 days following randomization	Day 0 to day 30
Mechanical ventilation-free days	Number of days without mechanical ventilation during the first 30 days following randomization	Day 0 to day 30
Blood lactate concentration	Arterial blood lactate levels	6 hours, 12 hours and 24 hours after randomization
SOFA score	Evolution of organ failure assessed using the Sequential Organ Failure Assessment (SOFA) score (minimum 0, maximum 24).	Baseline and day 3 after randomization
Cumulative fluid balance	Difference between total fluid intake and total fluid output	Day 0 to day 5
New-onset or persistent atrial fibrillation	Occurrence of new-onset atrial fibrillation or persistence of atrial fibrillation requiring clinical management.	Within 14 days after randomization
ICU and 90-day mortality	Vital status at Intensive Care Unit (ICU) discharge and at 90 days following randomization.	At day 3 and day 90 after randomization
Clinically significant bradycardia	Occurrence of bradycardia defined as heart rate < 50 bpm requiring therapeutic intervention	During the treatment period (until day 30)
Coma-free days	Number of days without coma up to day 30	Day 0 to day 30 or ICU discharge
ICU delirium	Occurrence of delirium during ICU stay assessed daily using the CAP-ICU in patients with RASS≥ -3	Daily until day 30 or ICU discharge

Collaborators and Investigators

• Sponsor: Hospices Civils de Lyon
• Collaborators: Centre Hospitalier Universitaire Dijon

Study record dates

Study Major Dates

• Study Start (Estimated): September 1, 2026
• Primary Completion (Estimated): October 1, 2028
• Study Completion (Estimated): December 1, 2028

Study Registration Dates

• First Submitted: April 22, 2026
• First Submitted That Met QC Criteria: April 29, 2026
• First Posted (Actual): May 6, 2026

Study Record Updates

• Last Update Posted (Actual): May 6, 2026
• Last Update Submitted That Met QC Criteria: April 29, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: dexmedetomidine; Septic shock; intensive care; sepsis; severe sepsis; vasoplegia; refractory septic shock; vasopressor resistance; alpha-2 adrenergic agonist
• Additional Relevant MeSH Terms: Vascular Diseases; Cardiovascular Diseases; Postoperative Complications; Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Shock; Pathological Conditions, Signs and Symptoms; Sepsis; Shock, Septic; Vasoplegia; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Azoles; Imidazoles; Dexmedetomidine
• Other Study ID Numbers: 69HCL25_0485; 2025-524122-18-00 (Ctis)

Drug and device information, study documents

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