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

29. april 2026 oppdatert av: 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.

Studieoversikt

Status

Har ikke rekruttert ennå

Forhold

Intervensjon / Behandling

Studietype

Intervensjonell

Registrering (Antatt)

360

Fase

  • Fase 3

Kontakter og plasseringer

Denne delen inneholder kontaktinformasjon for de som utfører studien, og informasjon om hvor denne studien blir utført.

Studiekontakt

Studer Kontakt Backup

Studiesteder

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

Deltakelseskriterier

Forskere ser etter personer som passer til en bestemt beskrivelse, kalt kvalifikasjonskriterier. Noen eksempler på disse kriteriene er en persons generelle helsetilstand eller tidligere behandlinger.

Kvalifikasjonskriterier

Alder som er kvalifisert for studier

  • Voksen
  • Eldre voksen

Tar imot friske frivillige

Nei

Beskrivelse

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

Studieplan

Denne delen gir detaljer om studieplanen, inkludert hvordan studien er utformet og hva studien måler.

Hvordan er studiet utformet?

Designdetaljer

  • Primært formål: Behandling
  • Tildeling: Randomisert
  • Intervensjonsmodell: Parallell tildeling
  • Masking: Ingen (Open Label)

Våpen og intervensjoner

Deltakergruppe / Arm
Intervensjon / Behandling
Eksperimentell: 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.
Legemiddel: 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
Annen: 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
Annen: Stardard care
fluid administration, source control, antibiotic therapy, and substitutive corticosteroid therapy in strict adherence to current guidelines

Hva måler studien?

Primære resultatmål

Resultatmål
Tiltaksbeskrivelse
Tidsramme
30-day mortality
Tidsramme: Day 30 after randomization
Vital status at day 30 after randomization.
Day 30 after randomization

Sekundære resultatmål

Resultatmål
Tiltaksbeskrivelse
Tidsramme
72-hour mortality
Tidsramme: 72 hours after randomization
Vital status at 72 hours after randomization
72 hours after randomization
Vasopressor exposure
Tidsramme: 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
Tidsramme: 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)
Tidsramme: 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
Tidsramme: 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
Tidsramme: 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
Tidsramme: 6 hours, 12 hours and 24 hours after randomization
Arterial blood lactate levels
6 hours, 12 hours and 24 hours after randomization
SOFA score
Tidsramme: 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
Tidsramme: 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
Tidsramme: 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
Tidsramme: 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
Tidsramme: 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
Tidsramme: 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
Tidsramme: 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

Samarbeidspartnere og etterforskere

Det er her du vil finne personer og organisasjoner som er involvert i denne studien.

Sponsor

Hospices Civils de Lyon

Samarbeidspartnere

Centre Hospitalier Universitaire Dijon

Studierekorddatoer

Disse datoene sporer fremdriften for innsending av studieposter og sammendragsresultater til ClinicalTrials.gov. Studieposter og rapporterte resultater gjennomgås av National Library of Medicine (NLM) for å sikre at de oppfyller spesifikke kvalitetskontrollstandarder før de legges ut på det offentlige nettstedet.

Studer hoveddatoer

Studiestart (Antatt)

1. september 2026

Primær fullføring (Antatt)

1. oktober 2028

Studiet fullført (Antatt)

1. desember 2028

Datoer for studieregistrering

Først innsendt

22. april 2026

Først innsendt som oppfylte QC-kriteriene

29. april 2026

Først lagt ut (Faktiske)

6. mai 2026

Oppdateringer av studieposter

Sist oppdatering lagt ut (Faktiske)

6. mai 2026

Siste oppdatering sendt inn som oppfylte QC-kriteriene

29. april 2026

Sist bekreftet

1. april 2026

Mer informasjon

Begreper knyttet til denne studien

Nøkkelord

Ytterligere relevante MeSH-vilkår

Andre studie-ID-numre

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

Legemiddel- og utstyrsinformasjon, studiedokumenter

Studerer et amerikansk FDA-regulert medikamentprodukt

Nei

Studerer et amerikansk FDA-regulert enhetsprodukt

Nei

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