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

Primary Purpose

Septic Shock, Vasopressor Resistance

Status

Terminated

Phase

Phase 3

Locations

France

Study Type

Interventional

Intervention

Dexmedetomidine 100 Mcg/mL Intravenous Solution

5% glucose Infusion solution

About this trial

This is an interventional treatment trial for Septic Shock

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Chu Dijon Bourgogne

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Dexmedetomidine

Placebo

Arm Description

Outcomes

Primary Outcome Measures

Relative change in mean blood pressure, expressed as a percentage

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)

Secondary Outcome Measures

Full Information

NCT ID

NCT03953677

First Posted

May 15, 2019

Last Updated

April 26, 2023

Sponsor

Centre Hospitalier Universitaire Dijon

1. Study Identification

Unique Protocol Identification Number

NCT03953677

Brief Title

Evaluation of the Effect of Dexmedetomidine on Phenylephrine Response During Refractory Septic Shock

Acronym

Adress-Pilot

Official Title

A Randomized Controlled Pilot Study Evaluating the Effect of Dexmedetomidine on Phenylephrine Response During Refractory Septic Shock

Study Type

Interventional

2. Study Status

Record Verification Date

April 2023

Overall Recruitment Status

Terminated

Why Stopped

Excess mortality in one arm of the study that led to discontinuation of enrollment

Study Start Date

October 27, 2019 (Actual)

Primary Completion Date

January 31, 2023 (Actual)

Study Completion Date

March 22, 2023 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Centre Hospitalier Universitaire Dijon

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Septic Shock, Vasopressor Resistance

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Parallel Assignment

Masking

ParticipantInvestigator

Allocation

Randomized

Enrollment

32 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Dexmedetomidine

Arm Type

Experimental

Arm Title

Placebo

Arm Type

Placebo Comparator

Intervention Type

Drug

Intervention Name(s)

Dexmedetomidine 100 Mcg/mL Intravenous Solution

Intervention Description

Continuous infusion of dexmedetomidine at 0.7 µg/kg/h for 2 hours and then 1 µg/kg/h at fixed dose

Intervention Type

Drug

Intervention Name(s)

5% glucose Infusion solution

Intervention Description

Continuous infusion of placebo (5% glucose) at 0.7 µg/kg/h for 2 hours and then 1 µg/kg/h at fixed dose

Primary Outcome Measure Information:

Title

Relative change in mean blood pressure, expressed as a percentage

Description

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)

Time Frame

6 hours after the end of the initial test

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Facility Information:

Facility Name

Chu Dijon Bourgogne

City

Dijon

ZIP/Postal Code

21000

Country

France

12. IPD Sharing Statement

Citations:

PubMed Identifier

36017005

Citation

Dargent A, Bourredjem A, Argaud L, Levy B, Fournel I, Cransac A, Badie J, Quintin L, Quenot JP. Dexmedetomidine to reduce vasopressor resistance in refractory septic shock: Protocol for a double-blind randomized controlled pilot trial (ADRESS Pilot study). Front Med (Lausanne). 2022 Aug 9;9:968274. doi: 10.3389/fmed.2022.968274. eCollection 2022.

Results Reference

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Evaluation of the Effect of Dexmedetomidine on Phenylephrine Response During Refractory Septic Shock

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