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

29 de abril de 2026 actualizado por: 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.

Descripción general del estudio

Estado

Aún no reclutando

Condiciones

Intervención / Tratamiento

Tipo de estudio

Intervencionista

Inscripción (Estimado)

360

Fase

  • Fase 3

Contactos y Ubicaciones

Esta sección proporciona los datos de contacto de quienes realizan el estudio e información sobre dónde se lleva a cabo este estudio.

Estudio Contacto

Copia de seguridad de contactos de estudio

Ubicaciones de estudio

  • Francia
      • Amiens, Francia, 80054
        • CHU Amiens-Picardie - Service de médecine intensive-réanimation
        • Contacto:
        • Investigador principal:
          • Yoann ZERBIB, MD
      • Chalon-sur-Saône, Francia, 71321
        • Centre Hospitalier Chalon-sur-Saône - Service de réanimation et surveillance continue
        • Investigador principal:
          • Thomas MALDINEY, MD
        • Contacto:
      • Dieppe, Francia, 76202
        • Centre Hospitalier de Dieppe - Service de réanimation et unité de soins continus
        • Contacto:
        • Investigador principal:
          • Antoine MARCHALOT, MD
      • Dijon, Francia, 21000
        • CHU Dijon Bourgogne - Service de médecine intensive et réanimation
        • Investigador principal:
          • Jean-Pierre QUENOT, MD
        • Contacto:
      • Garches, Francia, 92380
        • APHP - Hôpital Raymond-Poincaré - Service de Médecine intensive-réanimation
        • Investigador principal:
          • Djillali ANNANE, MD
        • Contacto:
      • La Roche-sur-Yon, Francia, 85925
        • Centre Hospitalier Départemental de Vendée - Service de réanimation polyvalente
        • Contacto:
        • Investigador principal:
          • Samuel GENSBURGER, MD
      • Le Mans, Francia, 72037
        • Centre Hospitalier Le Mans - Service de réanimation médico-chirurgicale
        • Investigador principal:
          • Jean-Christophe CALLAHAN, MD
        • Contacto:
      • Lyon, Francia, 69003
        • Hôpital Edouard Herriot - Service de Médecine intensive - reanimation
        • Investigador principal:
          • Laurent ARGAUD, MD
        • Contacto:
      • Lyon, Francia, 69004
        • Hôpital de la Croix Rousse - Service de médecine intensive et réanimation
        • Investigador principal:
          • Louis CHAUVELOT, MD
        • Contacto:
      • Lyon, Francia, 69007
        • Hôpital Saint Joseph Saint Luc - Service de réanimation
        • Investigador principal:
          • Emmanuel VIVIER, MD
        • Contacto:
      • Nice, Francia, 06200
        • Hôpital de l'archet - Service de médecine intensive et réanimation
        • Contacto:
        • Investigador principal:
          • Alan MOUROUGAYEN, MD
      • Pierre-Bénite, Francia, 69310
        • Service d'Anesthésie - Médecine Intensive - Réanimation Hôpital Lyon Sud
        • Contacto:
        • Investigador principal:
          • Auguste DARGENT, MD
      • Rennes, Francia, 35033
        • CHU de Rennes - Service de médecine intensive et réanimation
        • Investigador principal:
          • Nicolas TERZI, MD
        • Contacto:
      • Saint-Priest-en-Jarez, Francia, 42270
        • Hôpital Nord - CHU Saint Etienne - Service de médecine intensive
        • Contacto:
        • Investigador principal:
          • Sophie PERINEL, MD
      • Strasbourg, Francia, 67091
        • Nouvel Hôpital Civil - Service de médecine intensive et réanimation
        • Contacto:
        • Investigador principal:
          • Julie HELMS, Professor
      • Toulon, Francia, 83100
        • Centre Hospitalier Intercommunal de Toulon - Service de réanimation polyvalente
        • Investigador principal:
          • Jonathan CHELLY, MD
        • Contacto:
      • Trévenans, Francia, 90400
        • HOPITAL NORD FRANCHE-COMTE - Service de réanimation
        • Contacto:
        • Investigador principal:
          • Paul MONASTEROLO, MD
      • Villeurbanne, Francia, 69100
        • Médipôle Hôpital Privé Lyon Villeurbanne- Service de réanimation polyvalente
        • Contacto:
          • Stanislas LEDOCHOWSKI, MD
          • Número de teléfono: +334 87 65 01 88
          • Correo electrónico: sledochowski@scprea.fr
        • Investigador principal:
          • Stanislas LEDOCHOWSKI, MD

Criterios de participación

Los investigadores buscan personas que se ajusten a una determinada descripción, denominada criterio de elegibilidad. Algunos ejemplos de estos criterios son el estado de salud general de una persona o tratamientos previos.

Criterio de elegibilidad

Edades elegibles para estudiar

  • Adulto
  • Adulto Mayor

Acepta Voluntarios Saludables

No

Descripción

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

Plan de estudios

Esta sección proporciona detalles del plan de estudio, incluido cómo está diseñado el estudio y qué mide el estudio.

¿Cómo está diseñado el estudio?

Detalles de diseño

  • Propósito principal: Tratamiento
  • Asignación: Aleatorizado
  • Modelo Intervencionista: Asignación paralela
  • Enmascaramiento: Ninguno (etiqueta abierta)

Armas e Intervenciones

Grupo de participantes/brazo
Intervención / Tratamiento
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.
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
Otro: 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
Otro: Stardard care
fluid administration, source control, antibiotic therapy, and substitutive corticosteroid therapy in strict adherence to current guidelines

¿Qué mide el estudio?

Medidas de resultado primarias

Medida de resultado
Medida Descripción
Periodo de tiempo
30-day mortality
Periodo de tiempo: Day 30 after randomization
Vital status at day 30 after randomization.
Day 30 after randomization

Medidas de resultado secundarias

Medida de resultado
Medida Descripción
Periodo de tiempo
72-hour mortality
Periodo de tiempo: 72 hours after randomization
Vital status at 72 hours after randomization
72 hours after randomization
Vasopressor exposure
Periodo de tiempo: 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
Periodo de tiempo: 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)
Periodo de tiempo: 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
Periodo de tiempo: 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
Periodo de tiempo: 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
Periodo de tiempo: 6 hours, 12 hours and 24 hours after randomization
Arterial blood lactate levels
6 hours, 12 hours and 24 hours after randomization
SOFA score
Periodo de tiempo: 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
Periodo de tiempo: 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
Periodo de tiempo: 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
Periodo de tiempo: 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
Periodo de tiempo: 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
Periodo de tiempo: 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
Periodo de tiempo: 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

Colaboradores e Investigadores

Aquí es donde encontrará personas y organizaciones involucradas en este estudio.

Patrocinador

Hospices Civils de Lyon

Colaboradores

Centre Hospitalier Universitaire Dijon

Fechas de registro del estudio

Estas fechas rastrean el progreso del registro del estudio y los envíos de resultados resumidos a ClinicalTrials.gov. Los registros del estudio y los resultados informados son revisados ​​por la Biblioteca Nacional de Medicina (NLM) para asegurarse de que cumplan con los estándares de control de calidad específicos antes de publicarlos en el sitio web público.

Fechas importantes del estudio

Inicio del estudio (Estimado)

1 de septiembre de 2026

Finalización primaria (Estimado)

1 de octubre de 2028

Finalización del estudio (Estimado)

1 de diciembre de 2028

Fechas de registro del estudio

Enviado por primera vez

22 de abril de 2026

Primero enviado que cumplió con los criterios de control de calidad

29 de abril de 2026

Publicado por primera vez (Actual)

6 de mayo de 2026

Actualizaciones de registros de estudio

Última actualización publicada (Actual)

6 de mayo de 2026

Última actualización enviada que cumplió con los criterios de control de calidad

29 de abril de 2026

Última verificación

1 de abril de 2026

Más información

Términos relacionados con este estudio

Palabras clave

Términos MeSH relevantes adicionales

Otros números de identificación del estudio

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

Información sobre medicamentos y dispositivos, documentos del estudio

Estudia un producto farmacéutico regulado por la FDA de EE. UU.

No

Estudia un producto de dispositivo regulado por la FDA de EE. UU.

No

Esta información se obtuvo directamente del sitio web clinicaltrials.gov sin cambios. Si tiene alguna solicitud para cambiar, eliminar o actualizar los detalles de su estudio, comuníquese con register@clinicaltrials.gov. Tan pronto como se implemente un cambio en clinicaltrials.gov, también se actualizará automáticamente en nuestro sitio web. .

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