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Evaluation of the Effect of Dexmedetomidine on Phenylephrine Response During Refractory Septic Shock (Adress-Pilot)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT03953677
Recruitment Status : Recruiting
First Posted : May 16, 2019
Last Update Posted : March 3, 2020
Information provided by (Responsible Party):
Centre Hospitalier Universitaire Dijon

Tracking Information
First Submitted Date  ICMJE May 15, 2019
First Posted Date  ICMJE May 16, 2019
Last Update Posted Date March 3, 2020
Actual Study Start Date  ICMJE October 27, 2019
Estimated Primary Completion Date April 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 15, 2019)
Relative change in mean blood pressure, expressed as a percentage [ Time Frame: 6 hours after the end of the initial test ]
Relative variation in mean blood pressure between the basal value at the beginning of the test and the value reached at the dose of 6 µg/kg/min (%PAM0 = PAMd/PAM0 x100)
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
Descriptive Information
Brief Title  ICMJE Evaluation of the Effect of Dexmedetomidine on Phenylephrine Response During Refractory Septic Shock
Official Title  ICMJE A Randomized Controlled Pilot Study Evaluating the Effect of Dexmedetomidine on Phenylephrine Response During Refractory Septic Shock
Brief Summary

Septic shock is common in patients admitted to intensive care and hospital mortality occurs in close to 50% of these patients. In half of the cases, death occurs within the first 72 hours in a context of multiple organ failure that does not respond to conventional therapies, particularly circulatory therapies, despite increasing doses of catecholamines. Vasopressor resistance in septic patients defines refractory septic shock. In one study (Conrad et al. 2015), the increase in blood pressure observed with an infusion of increasing doses of phenylephrine (dose-response curve) made it possible to quickly and clearly identify patients resistant to vasopressors at a high risk of death by refractory shock (ROC AUC 0.92). This resistance is due in particular to a downregulation of α1 adrenergic receptors, linked to sympathetic hyper activation associated with septic shock. To date, there is no validated therapy in this situation. However, experimental data have shown that the administration of α2 agonists, usually used for their sedative (dexmedetomidine) or anti-hypertensive (clonidine) effect, normalizes sympathetic activity towards basal values. In animals, α2 agonists restore the sensitivity of alpha1 adrenergic receptors, resulting in improved vasopressor sensitivity and survival. In humans, a beneficial effect on mortality was suggested in the first trial testing dexmedetomidine in septic patients in 2017. This effect was observed especially in the most severe patients, suggesting a restoration of sensitivity to vasopressors.

The hypothesis is that the administration of dexmedetomidine in patients in refractory septic shock may improve response to phenylephrine and decrease resistance to vasopressors. This pilot study could lay the foundation for a randomized controlled trial.

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE
  • Septic Shock
  • Vasopressor Resistance
Intervention  ICMJE
  • Drug: Dexmedetomidine 100 Mcg/mL Intravenous Solution
    Continuous infusion of dexmedetomidine at 0.7 µg/kg/h for 2 hours and then 1 µg/kg/h at fixed dose
  • Drug: 5% glucose Infusion solution
    Continuous infusion of placebo (5% glucose) at 0.7 µg/kg/h for 2 hours and then 1 µg/kg/h at fixed dose
Study Arms  ICMJE
  • Experimental: Dexmedetomidine
    Intervention: Drug: Dexmedetomidine 100 Mcg/mL Intravenous Solution
  • Placebo Comparator: Placebo
    Intervention: Drug: 5% glucose Infusion solution
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: May 15, 2019)
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE July 2021
Estimated Primary Completion Date April 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Age ≥ 18 years old
  • Septic shock, defined by the "Sepsis-3" criteria

    • proven or suspected infection, with modification of the SOFA score ≥ 2 points,
    • with persistent hypotension requiring vasopressors to maintain MAP ≥ 65 mmHg
    • and a serum lactate level > 2 mmol/L despite adequate vascular filling
  • Adequate vascular filling: ≥ 30ml/kg, OR absence of preload-dependency criteria at time of assessment (respiratory variability of the inferior vena cava, passive leg lift, pulsed pressure variation)
  • Catecholamine resistance, defined by the need for a dose of norepinephrine ≥ 0,5 µg/kg/min for more than 2 consecutive hours within 24 hours of admission to intensive care unit
  • persistence of circulatory failure with at least one of the following criteria present in the 2 hours prior to randomisation: hyperlactatemia > 2mmol/l, and/or mottling (≥ 1 score), and/or oliguria (diuresis < 0,5 ml/kg/h over the last 2 hours)
  • Invasive Mechanical ventilation
  • Under sedation by midazolam or propofol
  • Informed consent obtained from a relative for patient included in an emergency
  • Patient affiliated to the national health insurance system

Exclusion Criteria:

  • Cardiac arrest before inclusion and occurring before septic shock criteria are met
  • Cardiac index < 2.2 l/min/m² after volume correction, or left ventricular ejection fraction < 40% on echocardiography
  • Bradycardia < 55 bpm (apart from treatment with β-blocker) or 2nd or 3rd degree BAV not equipped
  • Proven or suspected decompensation of coronary heart disease
  • Acute cerebrovascular condition within 2 weeks prior to inclusion
  • Severe hepatic insufficiency with TP and factor V <50% in the absence of DIC (disseminated intravascular coagulation)
  • Patient on adrenaline or vasopressors at the time of inclusion (epinephrine or vasopressin stopped prior to inclusion is not a criterion for non-inclusion)
  • Patient on non-selective MAOI iproniazid within 15 days of inclusion
  • Patient for whom a decision has been made to limit the use of therapies
  • Hypersensitivity to dexmedetomidine or phenylephrine
  • Patient on dexmedetomidine before inclusion
  • Person subject to a legal protection measure (curatorship, guardianship)
  • Person subject to limited judicial protection
  • Pregnant, parturient or breastfeeding woman
  • Patient with suspected or confirmed mesenteric ischemia
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Auguste DARGENT ext +33
Listed Location Countries  ICMJE France
Removed Location Countries  
Administrative Information
NCT Number  ICMJE NCT03953677
Other Study ID Numbers  ICMJE DARGENT APJ 2018
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Centre Hospitalier Universitaire Dijon
Study Sponsor  ICMJE Centre Hospitalier Universitaire Dijon
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Centre Hospitalier Universitaire Dijon
Verification Date May 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP