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

• Sponsor: University Hospital Inselspital, Berne (Other)
• Overall Status: Recruiting
• CT.gov ID: NCT04076826
• Collaborator: (none)
• Enrollment: 60
• Location: 1
• Arms: 2
• Anticipated Duration (Months): 33.9
• Patients Per Site Per Month: 1.8

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Sepsis-Associated Encephalopathy	Drug: Dexmedetomidine; Drug: Propofol or Midazolam; Diagnostic Test: Blood sampling	N/A

Study Design

• Study Type: Interventional
• Anticipated Enrollment: 60 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Prevention
• Official Title: Adjunctive Sedation With Dexmedetomidine for the Prevention of Severe Inflammation and Septic Encephalopathy: a Pilot Randomized Controlled Study.
• Actual Study Start Date: Sep 1, 2019
• Anticipated Primary Completion Date: Jun 30, 2022
• Anticipated Study Completion Date: Jun 30, 2022

Arms and Interventions

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).	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 ; 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.

Outcome Measures

Primary Outcome Measures

1. S100-ß [at 48 hours after randomization]

   Serum concentration of S100-ß

Secondary Outcome Measures

1. Neuron-specific enolase [first 3 days after randomization]

   Serum concentration of Neuron-specific enolase

2. Interleukin 1-beta [first 3 days after randomization]

   Serum concentration of Interleukin 1-beta

3. Interleukin 6 [first 3 days after randomization]

   Serum concentration of Interleukin 6

4. TNF alpha [first 3 days after randomization]

   Serum concentration of TNF alpha

5. Acetylcholinesterase activity [first 3 days after randomization]

   Acetylcholinesterase activity will be measured using a point-of-care device and reported as Units/grams Haemoglobin

6. Butyrylcholinesterase activity [first 3 days after randomization]

   Butyrylcholinesterase activity will be measured using a point-of-care device and reported as Units/L

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Inselspital, Bern University Hospital	Bern		Switzerland	3010

Sponsors and Collaborators

• University Hospital Inselspital, Berne

Investigators

• Principal Investigator: Luca Cioccari, MD, University Hospital Inselspital, Bern

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Luca Cioccari, Dr. med., University Hospital Inselspital, Berne
• ClinicalTrials.gov Identifier: NCT04076826
• Other Study ID Numbers: 4051
• First Posted: Sep 3, 2019
• Last Update Posted: Apr 28, 2021
• Last Verified: Apr 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• 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
• Keywords provided by Luca Cioccari, Dr. med., University Hospital Inselspital, Berne: Sepsis; Dexmedetomidine; Sedation; S-100beta; Encephalopathy
• Additional relevant MeSH terms: Brain Diseases; Sepsis-Associated Encephalopathy; Inflammation; Midazolam; Dexmedetomidine; Propofol

Study Results

No Results Posted as of Apr 28, 2021