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

29 aprile 2026 aggiornato da: Hospices Civils de Lyon

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.

Panoramica dello studio

Stato

Non ancora reclutamento

Condizioni

Intervento / Trattamento

Tipo di studio

Interventistico

Iscrizione (Stimato)

360

Fase

  • Fase 3

Contatti e Sedi

Questa sezione fornisce i recapiti di coloro che conducono lo studio e informazioni su dove viene condotto lo studio.

Contatto studio

Backup dei contatti dello studio

Luoghi di studio

  • Francia
      • Amiens, Francia, 80054
        • CHU Amiens-Picardie - Service de médecine intensive-réanimation
        • Contatto:
        • Investigatore principale:
          • Yoann ZERBIB, MD
      • Chalon-sur-Saône, Francia, 71321
        • Centre Hospitalier Chalon-sur-Saône - Service de réanimation et surveillance continue
        • Investigatore principale:
          • Thomas MALDINEY, MD
        • Contatto:
      • Dieppe, Francia, 76202
        • Centre Hospitalier de Dieppe - Service de réanimation et unité de soins continus
        • Contatto:
        • Investigatore principale:
          • Antoine MARCHALOT, MD
      • Dijon, Francia, 21000
        • CHU Dijon Bourgogne - Service de médecine intensive et réanimation
        • Investigatore principale:
          • Jean-Pierre QUENOT, MD
        • Contatto:
      • Garches, Francia, 92380
        • APHP - Hôpital Raymond-Poincaré - Service de Médecine intensive-réanimation
        • Investigatore principale:
          • Djillali ANNANE, MD
        • Contatto:
      • La Roche-sur-Yon, Francia, 85925
        • Centre Hospitalier Départemental de Vendée - Service de réanimation polyvalente
        • Contatto:
        • Investigatore principale:
          • Samuel GENSBURGER, MD
      • Le Mans, Francia, 72037
        • Centre Hospitalier Le Mans - Service de réanimation médico-chirurgicale
        • Investigatore principale:
          • Jean-Christophe CALLAHAN, MD
        • Contatto:
      • Lyon, Francia, 69003
        • Hôpital Edouard Herriot - Service de Médecine intensive - reanimation
        • Investigatore principale:
          • Laurent ARGAUD, MD
        • Contatto:
      • Lyon, Francia, 69004
        • Hôpital de la Croix Rousse - Service de médecine intensive et réanimation
        • Investigatore principale:
          • Louis CHAUVELOT, MD
        • Contatto:
      • Lyon, Francia, 69007
        • Hôpital Saint Joseph Saint Luc - Service de réanimation
        • Investigatore principale:
          • Emmanuel VIVIER, MD
        • Contatto:
      • Nice, Francia, 06200
        • Hôpital de l'archet - Service de médecine intensive et réanimation
        • Contatto:
        • Investigatore principale:
          • Alan MOUROUGAYEN, MD
      • Pierre-Bénite, Francia, 69310
        • Service d'Anesthésie - Médecine Intensive - Réanimation Hôpital Lyon Sud
        • Contatto:
        • Investigatore principale:
          • Auguste DARGENT, MD
      • Rennes, Francia, 35033
        • CHU de Rennes - Service de médecine intensive et réanimation
        • Investigatore principale:
          • Nicolas TERZI, MD
        • Contatto:
      • Saint-Priest-en-Jarez, Francia, 42270
        • Hôpital Nord - CHU Saint Etienne - Service de médecine intensive
        • Contatto:
        • Investigatore principale:
          • Sophie PERINEL, MD
      • Strasbourg, Francia, 67091
        • Nouvel Hôpital Civil - Service de médecine intensive et réanimation
        • Contatto:
        • Investigatore principale:
          • Julie HELMS, Professor
      • Toulon, Francia, 83100
        • Centre Hospitalier Intercommunal de Toulon - Service de réanimation polyvalente
        • Investigatore principale:
          • Jonathan CHELLY, MD
        • Contatto:
      • Trévenans, Francia, 90400
        • HOPITAL NORD FRANCHE-COMTE - Service de réanimation
        • Contatto:
        • Investigatore principale:
          • Paul MONASTEROLO, MD
      • Villeurbanne, Francia, 69100
        • Médipôle Hôpital Privé Lyon Villeurbanne- Service de réanimation polyvalente
        • Contatto:
        • Investigatore principale:
          • Stanislas LEDOCHOWSKI, MD

Criteri di partecipazione

I ricercatori cercano persone che corrispondano a una certa descrizione, chiamata criteri di ammissibilità. Alcuni esempi di questi criteri sono le condizioni generali di salute di una persona o trattamenti precedenti.

Criteri di ammissibilità

Età idonea allo studio

  • Adulto
  • Adulto più anziano

Accetta volontari sani

No

Descrizione

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

Piano di studio

Questa sezione fornisce i dettagli del piano di studio, compreso il modo in cui lo studio è progettato e ciò che lo studio sta misurando.

Come è strutturato lo studio?

Dettagli di progettazione

  • Scopo principale: Trattamento
  • Assegnazione: Randomizzato
  • Modello interventistico: Assegnazione parallela
  • Mascheramento: Nessuno (etichetta aperta)

Armi e interventi

Gruppo di partecipanti / Arm
Intervento / Trattamento
Sperimentale: 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.
Droga: 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
Altro: 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
Altro: Stardard care
fluid administration, source control, antibiotic therapy, and substitutive corticosteroid therapy in strict adherence to current guidelines

Cosa sta misurando lo studio?

Misure di risultato primarie

Misura del risultato
Misura Descrizione
Lasso di tempo
30-day mortality
Lasso di tempo: Day 30 after randomization
Vital status at day 30 after randomization.
Day 30 after randomization

Misure di risultato secondarie

Misura del risultato
Misura Descrizione
Lasso di tempo
72-hour mortality
Lasso di tempo: 72 hours after randomization
Vital status at 72 hours after randomization
72 hours after randomization
Vasopressor exposure
Lasso di tempo: 6, 12 and 24 hours after randomization
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
Lasso di tempo: From randomization to day 30
Proportion of patients requiring vasopressin or any therapy for refractory shock during follow-up
From randomization to day 30
Mean arterial pressure (MAP)
Lasso di tempo: Baseline, 6 hours, 12 hours and 24 hours after randomization
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
Lasso di tempo: Day 0 to day 30
Number of days without vasopressor therapy during the first 30 days following randomization
Day 0 to day 30
Mechanical ventilation-free days
Lasso di tempo: Day 0 to day 30
Number of days without mechanical ventilation during the first 30 days following randomization
Day 0 to day 30
Blood lactate concentration
Lasso di tempo: 6 hours, 12 hours and 24 hours after randomization
Arterial blood lactate levels
6 hours, 12 hours and 24 hours after randomization
SOFA score
Lasso di tempo: Baseline and day 3 after randomization
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
Lasso di tempo: Day 0 to day 5
Difference between total fluid intake and total fluid output
Day 0 to day 5
New-onset or persistent atrial fibrillation
Lasso di tempo: Within 14 days after randomization
Occurrence of new-onset atrial fibrillation or persistence of atrial fibrillation requiring clinical management.
Within 14 days after randomization
ICU and 90-day mortality
Lasso di tempo: At day 3 and day 90 after randomization
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
Lasso di tempo: During the treatment period (until day 30)
Occurrence of bradycardia defined as heart rate < 50 bpm requiring therapeutic intervention
During the treatment period (until day 30)
Coma-free days
Lasso di tempo: Day 0 to day 30 or ICU discharge
Number of days without coma up to day 30
Day 0 to day 30 or ICU discharge
ICU delirium
Lasso di tempo: Daily until day 30 or ICU discharge
Occurrence of delirium during ICU stay assessed daily using the CAP-ICU in patients with RASS≥ -3
Daily until day 30 or ICU discharge

Collaboratori e investigatori

Qui è dove troverai le persone e le organizzazioni coinvolte in questo studio.

Sponsor

Hospices Civils de Lyon

Collaboratori

Centre Hospitalier Universitaire Dijon

Studiare le date dei record

Queste date tengono traccia dell'avanzamento della registrazione dello studio e dell'invio dei risultati di sintesi a ClinicalTrials.gov. I record degli studi e i risultati riportati vengono esaminati dalla National Library of Medicine (NLM) per assicurarsi che soddisfino specifici standard di controllo della qualità prima di essere pubblicati sul sito Web pubblico.

Studia le date principali

Inizio studio (Stimato)

1 settembre 2026

Completamento primario (Stimato)

1 ottobre 2028

Completamento dello studio (Stimato)

1 dicembre 2028

Date di iscrizione allo studio

Primo inviato

22 aprile 2026

Primo inviato che soddisfa i criteri di controllo qualità

29 aprile 2026

Primo Inserito (Effettivo)

6 maggio 2026

Aggiornamenti dei record di studio

Ultimo aggiornamento pubblicato (Effettivo)

6 maggio 2026

Ultimo aggiornamento inviato che soddisfa i criteri QC

29 aprile 2026

Ultimo verificato

1 aprile 2026

Maggiori informazioni

Termini relativi a questo studio

Parole chiave

Termini MeSH pertinenti aggiuntivi

Altri numeri di identificazione dello studio

  • 69HCL25_0485
  • 2025-524122-18-00 (Ctis)

Informazioni su farmaci e dispositivi, documenti di studio

Studia un prodotto farmaceutico regolamentato dalla FDA degli Stati Uniti

No

Studia un dispositivo regolamentato dalla FDA degli Stati Uniti

No

Queste informazioni sono state recuperate direttamente dal sito web clinicaltrials.gov senza alcuna modifica. In caso di richieste di modifica, rimozione o aggiornamento dei dettagli dello studio, contattare register@clinicaltrials.gov. Non appena verrà implementata una modifica su clinicaltrials.gov, questa verrà aggiornata automaticamente anche sul nostro sito web .

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