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

29. April 2026 aktualisiert von: 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.

Studienübersicht

Status

Noch keine Rekrutierung

Bedingungen

Intervention / Behandlung

Studientyp

Interventionell

Einschreibung (Geschätzt)

360

Phase

  • Phase 3

Kontakte und Standorte

Dieser Abschnitt enthält die Kontaktdaten derjenigen, die die Studie durchführen, und Informationen darüber, wo diese Studie durchgeführt wird.

Studienkontakt

Studieren Sie die Kontaktsicherung

Studienorte

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

Teilnahmekriterien

Forscher suchen nach Personen, die einer bestimmten Beschreibung entsprechen, die als Auswahlkriterien bezeichnet werden. Einige Beispiele für diese Kriterien sind der allgemeine Gesundheitszustand einer Person oder frühere Behandlungen.

Zulassungskriterien

Studienberechtigtes Alter

  • Erwachsene
  • Älterer Erwachsener

Akzeptiert gesunde Freiwillige

Nein

Beschreibung

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

Studienplan

Dieser Abschnitt enthält Einzelheiten zum Studienplan, einschließlich des Studiendesigns und der Messung der Studieninhalte.

Wie ist die Studie aufgebaut?

Designdetails

  • Hauptzweck: Behandlung
  • Zuteilung: Zufällig
  • Interventionsmodell: Parallele Zuordnung
  • Maskierung: Keine (Offenes Etikett)

Waffen und Interventionen

Teilnehmergruppe / Arm
Intervention / Behandlung
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.
Arzneimittel: 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
Sonstiges: 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
Sonstiges: Stardard care
fluid administration, source control, antibiotic therapy, and substitutive corticosteroid therapy in strict adherence to current guidelines

Was misst die Studie?

Primäre Ergebnismessungen

Ergebnis Maßnahme
Maßnahmenbeschreibung
Zeitfenster
30-day mortality
Zeitfenster: Day 30 after randomization
Vital status at day 30 after randomization.
Day 30 after randomization

Sekundäre Ergebnismessungen

Ergebnis Maßnahme
Maßnahmenbeschreibung
Zeitfenster
72-hour mortality
Zeitfenster: 72 hours after randomization
Vital status at 72 hours after randomization
72 hours after randomization
Vasopressor exposure
Zeitfenster: 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
Zeitfenster: 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)
Zeitfenster: 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
Zeitfenster: 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
Zeitfenster: 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
Zeitfenster: 6 hours, 12 hours and 24 hours after randomization
Arterial blood lactate levels
6 hours, 12 hours and 24 hours after randomization
SOFA score
Zeitfenster: 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
Zeitfenster: 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
Zeitfenster: 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
Zeitfenster: 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
Zeitfenster: 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
Zeitfenster: 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
Zeitfenster: 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

Mitarbeiter und Ermittler

Hier finden Sie Personen und Organisationen, die an dieser Studie beteiligt sind.

Sponsor

Hospices Civils de Lyon

Mitarbeiter

Centre Hospitalier Universitaire Dijon

Studienaufzeichnungsdaten

Diese Daten verfolgen den Fortschritt der Übermittlung von Studienaufzeichnungen und zusammenfassenden Ergebnissen an ClinicalTrials.gov. Studienaufzeichnungen und gemeldete Ergebnisse werden von der National Library of Medicine (NLM) überprüft, um sicherzustellen, dass sie bestimmten Qualitätskontrollstandards entsprechen, bevor sie auf der öffentlichen Website veröffentlicht werden.

Haupttermine studieren

Studienbeginn (Geschätzt)

1. September 2026

Primärer Abschluss (Geschätzt)

1. Oktober 2028

Studienabschluss (Geschätzt)

1. Dezember 2028

Studienanmeldedaten

Zuerst eingereicht

22. April 2026

Zuerst eingereicht, das die QC-Kriterien erfüllt hat

29. April 2026

Zuerst gepostet (Tatsächlich)

6. Mai 2026

Studienaufzeichnungsaktualisierungen

Letztes Update gepostet (Tatsächlich)

6. Mai 2026

Letztes eingereichtes Update, das die QC-Kriterien erfüllt

29. April 2026

Zuletzt verifiziert

1. April 2026

Mehr Informationen

Begriffe im Zusammenhang mit dieser Studie

Schlüsselwörter

Zusätzliche relevante MeSH-Bedingungen

Andere Studien-ID-Nummern

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

Arzneimittel- und Geräteinformationen, Studienunterlagen

Studiert ein von der US-amerikanischen FDA reguliertes Arzneimittelprodukt

Nein

Studiert ein von der US-amerikanischen FDA reguliertes Geräteprodukt

Nein

Diese Informationen wurden ohne Änderungen direkt von der Website clinicaltrials.gov abgerufen. Wenn Sie Ihre Studiendaten ändern, entfernen oder aktualisieren möchten, wenden Sie sich bitte an register@clinicaltrials.gov. Sobald eine Änderung auf clinicaltrials.gov implementiert wird, wird diese automatisch auch auf unserer Website aktualisiert .

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