Adjunctive Sedation With Dexmedetomidine for the Prevention of Severe Inflammation and Septic Encephalopathy (ADVISE)

Adjunctive Sedation With Dexmedetomidine for the Prevention of Severe Inflammation and Septic Encephalopathy: a Pilot Randomized Controlled Study.

Septic encephalopathy (SE) is defined as acute cerebral dysfunction in patients with sepsis or septic shock. SE occurs in up to 50% of critically ill patients with sepsis and is associated with a high mortality and morbidity. The pathophysiology of SE is complex and involves increased levels of inflammatory mediators such as tumor necrosis factor (TNF)-α, Interleukin (IL)-1 and IL-6, leading to blood brain barrier dysfunction and neuronal inflammation. Several biomarkers of neuronal injury have been proposed to identify patients with SE. Of these biomarkers, S100-β has the highest sensitivity and specificity.

Sedation with Dexmedetomidine (DEX) is a promising strategy for the management of these patients, as DEX has been shown to decrease the production of inflammatory mediators in experimental models of sepsis. In clinical studies, DEX lowers the incidence of delirium and critical illness polyneuropathy. However, its effectiveness in treatment and prevention of SE remains unclear.

The aim of the present study is to investigate the effect of two standard sedation protocols (Dexmedetomidine sedation vs. Propofol / Midazolam) on serum markers of SE in critically ill patients with sepsis who require sedation and mechanical ventilation.

Study Overview

• Status: Completed
• Conditions: Sepsis-Associated Encephalopathy
• Intervention / Treatment: Drug: Dexmedetomidine; Diagnostic test: Blood sampling; Drug: Propofol or Midazolam

• Study Type: Interventional
• Enrollment (Actual): 70
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Switzerland
  • Bern, Switzerland, 3010
    • Inselspital, Bern University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• The participant is aged 18 years or older
• The participant has been intubated and is receiving mechanical ventilation
• The participant requires sedative medication for comfort, safety or to facilitate the delivery of life support measures
• The participant has either a central venous or an arterial catheter inserted within 24 hours of admission
• The participant has a diagnosis of sepsis based on the recent SEPSIS-3 consensus clinical criteria.

Exclusion Criteria:

• Age < 18 years
• The treating physician believes that the participant will remain intubated for <24 hours or the participant has been intubated for diagnostic or therapeutic procedures as the sole reason for mechanical ventilation.
• Participants with any of the following admission diagnosis: acute cerebral vascular event, traumatic brain injury, epilepsy, hypoxic brain injury, meningitis, encephalitis
• Participants with history of melanoma (S 100-β is elevated in melanoma participants)
• Participants with schizophrenia or other chronic psychiatric conditions
• Admission for drug overdose
• Planned administration of ongoing neuromuscular blockade
• Heart rate < 55 / min or an atrioventricular block > grade 2a in the absence of a functioning pacemaker
• Known hypersensitivity or allergy to any of the sedative medications used in this study.
• DNR (do not resuscitate) or DNI (do not intubate) orders
• Death is deemed to be imminent or inevitable during this admission and either the attending physician, participant or substitute decision maker is not committed to active treatment
• Women who are pregnant or breast feeding
• Known or suspected non-compliance, drug or severe alcohol abuse
• Inability of the participant to understand the procedures of the study, e.g. due to language problems, psychological disorders, or dementia
• Previous enrolment into the current study
• Enrolment of the investigator, his/her family members, employees and other dependent persons

Study Plan

How is the study designed?

Design Details

• Primary Purpose: PREVENTION
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Protocol A (Dexmedetomidine); Dexmedetomidine will be administered in accordance with hospital standard operating procedures (SOP).	Drug: Dexmedetomidine; Dexmedetomidine infusion will be commenced in accordance with the hospital's local sedation protocol, without a loading dose, at a rate of 0.1 - 1.4 mcg/kg/hour to maintain sedation as per Richmond Agitation-Sedation Scale (RASS) sedation range specified by the treating clinician. Infusion will be continued until sedation is no longer clinically indicated up to a maximum of 7 days after enrolment.; Other Names: Protocol A; Diagnostic test: Blood sampling; In all participants, we will collect blood samples for measurement of neuronal and systemic biomarkers of inflammation at randomization (baseline), at day 1, day 2 and day 3 after randomization.
ACTIVE_COMPARATOR: Protocol B (Propofol / Midazolam); Propofol and/or Midazolam will be administered in accordance with hospital standard operating procedures (SOP).	Diagnostic test: Blood sampling; In all participants, we will collect blood samples for measurement of neuronal and systemic biomarkers of inflammation at randomization (baseline), at day 1, day 2 and day 3 after randomization.; Drug: Propofol or Midazolam; Propofol and/or Midazolam will be used according to Hospital guidelines to maintain sedation as per Richmond Agitation-Sedation Scale (RASS) sedation range specified by the treating clinician.; Other Names: Protocol B

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
S100-ß	Serum concentration of S100-ß	at 48 hours after randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Neuron-specific enolase	Serum concentration of Neuron-specific enolase	first 3 days after randomization
Interleukin 1-beta	Serum concentration of Interleukin 1-beta	first 3 days after randomization
Interleukin 6	Serum concentration of Interleukin 6	first 3 days after randomization
TNF alpha	Serum concentration of TNF alpha	first 3 days after randomization
Acetylcholinesterase activity	Acetylcholinesterase activity will be measured using a point-of-care device and reported as Units/grams Haemoglobin	first 3 days after randomization
Butyrylcholinesterase activity	Butyrylcholinesterase activity will be measured using a point-of-care device and reported as Units/L	first 3 days after randomization

Collaborators and Investigators

• Sponsor: University Hospital Inselspital, Berne

Study record dates

Study Major Dates

• Study Start (ACTUAL): September 1, 2019
• Primary Completion (ACTUAL): June 17, 2022
• Study Completion (ACTUAL): July 8, 2022

Study Registration Dates

• First Submitted: August 22, 2019
• First Submitted That Met QC Criteria: August 29, 2019
• First Posted (ACTUAL): September 3, 2019

Study Record Updates

• Last Update Posted (ACTUAL): February 13, 2023
• Last Update Submitted That Met QC Criteria: February 10, 2023
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Keywords: Sedation; Sepsis; Dexmedetomidine; Encephalopathy; S-100beta
• Additional Relevant MeSH Terms: Pathologic Processes; Central Nervous System Diseases; Nervous System Diseases; Inflammation; Brain Diseases; Sepsis-Associated Encephalopathy; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Analgesics, Non-Narcotic; Adrenergic alpha-2 Receptor Agonists; Adrenergic alpha-Agonists; Adrenergic Agonists; Tranquilizing Agents; Psychotropic Drugs; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Midazolam; Propofol; Dexmedetomidine
• Other Study ID Numbers: 4051

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No