Septic Shock, Vasopressor Resistance
Conditions
Keywords
Septic shock, refractory septic shock, sepsis, severe sepsis, intensive care, vasoplegia, vasopressor resistance, dexmedetomidine, alpha-2 adrenergic agonist
Brief summary
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.
Interventions
DRUGDexmedetomidine 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
OTHERStardard care
fluid administration, source control, antibiotic therapy, and substitutive corticosteroid therapy in strict adherence to current guidelines
Sponsors
Hospices Civils de Lyon
Centre Hospitalier Universitaire Dijon
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
A prospective, randomized (1 :1), open-label, parallel-group, multicenter superiority trial comparing an experimental intervention to standard care
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 30-day mortality | Day 30 after randomization | Vital status at day 30 after randomization. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| New-onset or persistent atrial fibrillation | Within 14 days after randomization | Occurrence of new-onset atrial fibrillation or persistence of atrial fibrillation requiring clinical management. |
| ICU and 90-day mortality | At day 3 and day 90 after randomization | Vital status at Intensive Care Unit (ICU) discharge and at 90 days following randomization. |
| Clinically significant bradycardia | During the treatment period (until day 30) | Occurrence of bradycardia defined as heart rate \< 50 bpm requiring therapeutic intervention |
| Coma-free days | Day 0 to day 30 or ICU discharge | Number of days without coma up to day 30 |
| ICU delirium | Daily until day 30 or ICU discharge | Occurrence of delirium during ICU stay assessed daily using the CAP-ICU in patients with RASS≥ -3 |
| 72-hour mortality | 72 hours after randomization | Vital status at 72 hours after randomization |
| Vasopressor exposure | 6, 12 and 24 hours after randomization | Cumulative vasopressor dose and peak vasopressor dose expressed as norepinephrine-equivalent dose (NEE score) |
| Use of vasopressin or recue therapies | From randomization to day 30 | Proportion of patients requiring vasopressin or any therapy for refractory shock during follow-up |
| Mean arterial pressure (MAP) | 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 |
| Vasopressor-free days | Day 0 to day 30 | Number of days without vasopressor therapy during the first 30 days following randomization |
| Mechanical ventilation-free days | Day 0 to day 30 | Number of days without mechanical ventilation during the first 30 days following randomization |
| Blood lactate concentration | 6 hours, 12 hours and 24 hours after randomization | Arterial blood lactate levels |
| Cumulative fluid balance | Day 0 to day 5 | Difference between total fluid intake and total fluid output |
| SOFA score | Baseline and day 3 after randomization | Evolution of organ failure assessed using the Sequential Organ Failure Assessment (SOFA) score (minimum 0, maximum 24). |
Countries
France
Contacts
CONTACTAuguste DARGENT, Doctor
CONTACTJean-Pierre QUENOT, Professor
Outcome results
None listed