Efficacy of the Alpha 2 Agonist Dexmedetomidine for Sympathetic Deactivation in REfractory Septic Shock
ADRESS
2 other identifiers
interventional
360
1 country
18
Brief Summary
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.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P50-P75 for phase_3
Started Sep 2026
18 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
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Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
April 22, 2026
CompletedFirst Posted
Study publicly available on registry
May 6, 2026
CompletedStudy Start
First participant enrolled
September 1, 2026
ExpectedPrimary Completion
Last participant's last visit for primary outcome
October 1, 2028
Study Completion
Last participant's last visit for all outcomes
December 1, 2028
May 6, 2026
April 1, 2026
2.1 years
April 22, 2026
April 29, 2026
Conditions
Keywords
Outcome Measures
Primary Outcomes (1)
30-day mortality
Vital status at day 30 after randomization.
Day 30 after randomization
Secondary Outcomes (14)
72-hour mortality
72 hours after randomization
Vasopressor exposure
6, 12 and 24 hours after randomization
Use of vasopressin or recue therapies
From randomization to day 30
Mean arterial pressure (MAP)
Baseline, 6 hours, 12 hours and 24 hours after randomization
Vasopressor-free days
Day 0 to day 30
- +9 more secondary outcomes
Study Arms (2)
Dexmedetomidine 100 µg/Ml
EXPERIMENTALPatients 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.
Standard care
OTHERPatients 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
Interventions
Continuous infusion on dexmedetomidine at 0,7 μg/kg/h for 2 hours and then 1 μg/kg/h at fixed dose
fluid administration, source control, antibiotic therapy, and substitutive corticosteroid therapy in strict adherence to current guidelines
Eligibility Criteria
You may qualify if:
- 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
You may not qualify if:
- 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
- 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)
- Pregant or breastfeeding woman
Contact the study team to confirm eligibility.
Sponsors & Collaborators
- Hospices Civils de Lyonlead
- Centre Hospitalier Universitaire Dijoncollaborator
Study Sites (18)
CHU Amiens-Picardie - Service de médecine intensive-réanimation
Amiens, 80054, France
Centre Hospitalier Chalon-sur-Saône - Service de réanimation et surveillance continue
Chalon-sur-Saône, 71321, France
Centre Hospitalier de Dieppe - Service de réanimation et unité de soins continus
Dieppe, 76202, France
CHU Dijon Bourgogne - Service de médecine intensive et réanimation
Dijon, 21000, France
APHP - Hôpital Raymond-Poincaré - Service de Médecine intensive-réanimation
Garches, 92380, France
Centre Hospitalier Départemental de Vendée - Service de réanimation polyvalente
La Roche-sur-Yon, 85925, France
Centre Hospitalier Le Mans - Service de réanimation médico-chirurgicale
Le Mans, 72037, France
Hôpital Edouard Herriot - Service de Médecine intensive - reanimation
Lyon, 69003, France
Hôpital de la Croix Rousse - Service de médecine intensive et réanimation
Lyon, 69004, France
Hôpital Saint Joseph Saint Luc - Service de réanimation
Lyon, 69007, France
Hôpital de l'archet - Service de médecine intensive et réanimation
Nice, 06200, France
Service d'Anesthésie - Médecine Intensive - Réanimation Hôpital Lyon Sud
Pierre-Bénite, 69310, France
CHU de Rennes - Service de médecine intensive et réanimation
Rennes, 35033, France
Hôpital Nord - CHU Saint Etienne - Service de médecine intensive
Saint-Priest-en-Jarez, 42270, France
Nouvel Hôpital Civil - Service de médecine intensive et réanimation
Strasbourg, 67091, France
Centre Hospitalier Intercommunal de Toulon - Service de réanimation polyvalente
Toulon, 83100, France
HOPITAL NORD FRANCHE-COMTE - Service de réanimation
Trévenans, 90400, France
Médipôle Hôpital Privé Lyon Villeurbanne- Service de réanimation polyvalente
Villeurbanne, 69100, France
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Central Study Contacts
Study Design
- Study Type
- interventional
- Phase
- phase 3
- Allocation
- RANDOMIZED
- Masking
- NONE
- Purpose
- TREATMENT
- Intervention Model
- PARALLEL
- Sponsor Type
- OTHER
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
April 22, 2026
First Posted
May 6, 2026
Study Start (Estimated)
September 1, 2026
Primary Completion (Estimated)
October 1, 2028
Study Completion (Estimated)
December 1, 2028
Last Updated
May 6, 2026
Record last verified: 2026-04