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

Starting soon · Phase 3

Conditions studied: Septic Shock, Vasopressor Resistance

In brief

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.

Key facts

Study ID: NCT07569536
Run by: Hospices Civils de Lyon
People needed: 360
Starts: 2026-09-01
Expected to finish: 2028-12-01
Last updated by the study team: 2026-05-06

Who can join

Age: 18 and older. Sex: any. Healthy volunteers: not accepted.

You may qualify if…

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

You may not qualify if…

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

Where it is running

CHU Amiens-Picardie - Service de médecine intensive-réanimation — Amiens, France
Centre Hospitalier Chalon-sur-Saône - Service de réanimation et surveillance continue — Chalon-sur-Saône, France
Centre Hospitalier de Dieppe - Service de réanimation et unité de soins continus — Dieppe, France
CHU Dijon Bourgogne - Service de médecine intensive et réanimation — Dijon, France
APHP - Hôpital Raymond-Poincaré - Service de Médecine intensive-réanimation — Garches, France
Centre Hospitalier Départemental de Vendée - Service de réanimation polyvalente — La Roche-sur-Yon, France
Centre Hospitalier Le Mans - Service de réanimation médico-chirurgicale — Le Mans, France
Hôpital Edouard Herriot - Service de Médecine intensive - reanimation — Lyon, France
Hôpital de la Croix Rousse - Service de médecine intensive et réanimation — Lyon, France
Hôpital Saint Joseph Saint Luc - Service de réanimation — Lyon, France
Hôpital de l'archet - Service de médecine intensive et réanimation — Nice, France
Service d'Anesthésie - Médecine Intensive - Réanimation Hôpital Lyon Sud — Pierre-Bénite, France
CHU de Rennes - Service de médecine intensive et réanimation — Rennes, France
Hôpital Nord - CHU Saint Etienne - Service de médecine intensive — Saint-Priest-en-Jarez, France
Nouvel Hôpital Civil - Service de médecine intensive et réanimation — Strasbourg, France
Centre Hospitalier Intercommunal de Toulon - Service de réanimation polyvalente — Toulon, France
HOPITAL NORD FRANCHE-COMTE - Service de réanimation — Trévenans, France
Médipôle Hôpital Privé Lyon Villeurbanne- Service de réanimation polyvalente — Villeurbanne, France

Full record on ClinicalTrials.gov

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