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

2026年4月29日 更新者：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.

調査の概要

状態

まだ募集していません

条件

介入・治療

研究の種類

介入

入学 (推定)

360

段階

  • フェーズ 3

連絡先と場所

このセクションには、調査を実施する担当者の連絡先の詳細と、この調査が実施されている場所に関する情報が記載されています。

研究連絡先

研究連絡先のバックアップ

研究場所

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

参加基準

研究者は、適格基準と呼ばれる特定の説明に適合する人を探します。これらの基準のいくつかの例は、人の一般的な健康状態または以前の治療です。

適格基準

就学可能な年齢

  • 大人
  • 高齢者

健康ボランティアの受け入れ

いいえ

説明

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

研究計画

このセクションでは、研究がどのように設計され、研究が何を測定しているかなど、研究計画の詳細を提供します。

研究はどのように設計されていますか？

デザインの詳細

  • 主な目的：処理
  • 割り当て：ランダム化
  • 介入モデル：並列代入
  • マスキング：なし（オープンラベル）

武器と介入

参加者グループ / アーム
介入・治療
実験的：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.
薬：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
他の：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
他の：Stardard care
fluid administration, source control, antibiotic therapy, and substitutive corticosteroid therapy in strict adherence to current guidelines

この研究は何を測定していますか？

主要な結果の測定

結果測定
メジャーの説明
時間枠
30-day mortality
時間枠：Day 30 after randomization
Vital status at day 30 after randomization.
Day 30 after randomization

二次結果の測定

結果測定
メジャーの説明
時間枠
72-hour mortality
時間枠：72 hours after randomization
Vital status at 72 hours after randomization
72 hours after randomization
Vasopressor exposure
時間枠：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
時間枠：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)
時間枠：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
時間枠：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
時間枠：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
時間枠：6 hours, 12 hours and 24 hours after randomization
Arterial blood lactate levels
6 hours, 12 hours and 24 hours after randomization
SOFA score
時間枠：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
時間枠：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
時間枠：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
時間枠：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
時間枠：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
時間枠：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
時間枠：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

協力者と研究者

ここでは、この調査に関係する人々や組織を見つけることができます。

スポンサー

Hospices Civils de Lyon

協力者

Centre Hospitalier Universitaire Dijon

研究記録日

これらの日付は、ClinicalTrials.gov への研究記録と要約結果の提出の進捗状況を追跡します。研究記録と報告された結果は、国立医学図書館 (NLM) によって審査され、公開 Web サイトに掲載される前に、特定の品質管理基準を満たしていることが確認されます。

主要日程の研究

研究開始 (推定)

2026年9月1日

一次修了 (推定)

2028年10月1日

研究の完了 (推定)

2028年12月1日

試験登録日

最初に提出

2026年4月22日

QC基準を満たした最初の提出物

2026年4月29日

最初の投稿 (実際)

2026年5月6日

学習記録の更新

投稿された最後の更新 (実際)

2026年5月6日

QC基準を満たした最後の更新が送信されました

2026年4月29日

最終確認日

2026年4月1日

詳しくは

本研究に関する用語

キーワード

追加の関連 MeSH 用語

その他の研究ID番号

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

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米国FDA規制医薬品の研究

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米国FDA規制機器製品の研究

いいえ

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