Neuroprotection With Dexmedetomidine in Patients Undergoing Elective Cardiac or Abdominal Surgery (Neuprodex)

Neuroprotection With Dexmedetomidine in Patients Undergoing Elective Cardiac or Abdominal Surgery (NEUPRODEX)

The drug Dexmedetomidine will be investigated in 72 patients (men and women) undergoing elective cardiac or abdominal surgery. The study medication will be administered perioperatively by intravenous infusion continuously (at the longest 48 h) to prevent/reduce the rate of Delirium and the incidence of postoperative cognitive deficit (POCD).

A non-surgical control group of 15 ASA II/III- patients from Berlin and surrounding area is collected for measuring the learning experience during the cognitive testings. The participants are matched on age, education, and gender to the study patients.

Cognitive testings are performed in patients of the study group (n= 72) and the control group (n= 15) to evaluate deficits in their cognitive areas (POCD (Postoperative cognitive deficit)) at three different time points up to three months.

Study Overview

• Status: Completed
• Conditions: Delirium; Postoperative Cognitive Deficit (POCD)
• Intervention / Treatment: Drug: Dexmedetomidine (Dexdor®); Drug: 0.9% Sodium Chloride

• Study Type: Interventional
• Enrollment (Actual): 78
• Phase: Phase 4

Contacts and Locations

Study Locations

• Germany
  • Berlin, Germany, 13353
    • Department of Anesthesiology and Operative Intensive Care Medicine, Campus Charité Mitte and Campus Virchow - Klinikum, Charité- Universitätsmedizin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 58 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Study Group:

Inclusion Criteria:

1. Patients aged ≥ 60 years
2. Male and female patients undergoing elective cardiac (elective CABG-surgery without valve surgery with left ventricular ejection fraction ≥ 30%) or pancreatic or hepatic or gastric or intestinal surgery of both Campus Charité Mitte and Campus Virchow - Klinikum, Charité - Universitätsmedizin Berlin
3. Offered patient information and written consent by the patient (according to German Drug Law § 40 (1) 3b)
4. Premedication only with benzodiazepines
5. Pain therapy during the operation with regional procedures and/or Sufentanil/Fentanyl
6. Anesthesia in cardio surgery according to Heart-Lung-Apparatus
7. Anesthesia with hypnotic agent Propofol
8. Pain therapy after operation according to S3-Guideline
9. Postoperative medication for anxiolysis only with benzodiazepines

Exclusion Criteria:

1. Known drug intolerance/allergy: dexmedetomidine or to other ingredients
2. Lacking willingness to save and hand out pseudonymised data within the clinical trial
3. Accommodation in an institution due to an official or judicial order (according to AMG §40 (1) 4)
4. Employee of the Charité - Universitätsmedizin Berlin CVK/CCM
5. Illiteracy
6. Inability to speak and/or read German
7. Minimal mental status examination (MMSE) < 24
8. Severe hearing loss or visual impairment
9. Acute brain injury
10. Intracranial haemorrhage within one year before participation in the study
11. Manifest psychiatric disease
12. Known illicit substance abuse
13. Acute intoxication
14. For women: Pregnancy or positive pregnancy test within the preoperative screening
15. Homeless or other circumstances, where the patient would not be reachable by telephone or postal services for the 3-months follow up
16. Participation in another interventional clinical trial according to the German Drug Law at time of inclusion and during the trial
17. Acute circulatory failure at time of randomisation (severe hypotension with mean arterial pressure < 55 mmHg despite vasopressors or optimal preload)
18. AV-conduction-block II or III (unless pacemaker installed)
19. Severe bradycardia (heart-rate < 50 bpm, preoperative, permanent)
20. Spinal cord injury with known autonomic dysregulation
21. Preoperative acute cerebrovascular event with neurologic residues
22. Liver insufficiency (Child C cirrhosis, MELD Score > 17)
23. Application of Remifentanil during the operation
24. Deep sedation (RASS, -4 to -5)
25. Administration of Clonidine during administration of the study drug
26. Additional administration of Dexmedetomidine within 3 months after study inclusion

Control Group:

Inclusion Criteria:

1. Patients aged ≥ 60 years of European descent (Caucasian)
2. Male or female patients with ASA II+III
3. ASA II+III-patients, for which no operation is planned within the next year
4. No operation in the last half year before study inclusion
5. Offered patient information and written informed consent

Exclusion Criteria

1. Minimal mental status examination (MMSE) < 24
2. Missing informed consent for saving and hand out pseudonymous data
3. Neuropsychiatric morbidity, which limits the conduction of the neurocognitive testing
4. Anacusis or Hypoacusis, which limits the conduction of the neurocognitive testing
5. Taking psychothropic drugs (including sleep-inducing drug and benzodiazepine) on a regular basis and other substances, which limit the conduction of the neurocognitive testing

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Study group; Application of Dexmedetomidine (Dexdor®) perioperatively for a maximum of 48 hours Dosing Scheme: during operation and mechanical ventilation: 0,7μg/kgABW/h; recovery time until extubation: 0,4μg/kgABW/h; after extubation: 0,2-1,4μg/kgABW/h	Drug: Dexmedetomidine (Dexdor®); Dexmedetomidine (Dexdor 100 micrograms/ml concentrate for solution for infusion)
Placebo Comparator: Control group; Application of placebo for a maximum of 48 hours	Drug: 0.9% Sodium Chloride; Solution for infusion: Sodium Chloride : 9.0 g/l; Each ml contains 9 mg sodium chloride mmol/l : Na+ : 154. Cl-: 154.
No Intervention: POCD control group; A non-surgical control group of 15 ASA II/III- patients is collected for measuring the learning experience during the cognitive testings. The participants are matched on age, education, and gender to the study patients.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of postoperative delirium	Incidence of postoperative delirium measured with the Confusion Assessment Method for the ICU (CAM-ICU) or the Confusion Assessment Method (CAM)	Until the 5th postoperative day

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Intraoperative cerebral oxymetry		At time of surgery
Incidence of subsyndromal delirium and severity of postoperative delirium	Incidence of Subsyndromal Delirium (SSD) and severity of postoperative Delirium measured with the Intensive Care Delirium Screening Checklist (ICDSC)	Until the 14th postoperative day/discharge
Duration of delirium in the intensive care unit	Duration of intensive care unit-delirium measured with the Confusion Assessment Method for the ICU (CAM-ICU) and the Intensive Care Delirium Screening Checklist (ICDSC)	Until the 14th postoperative day/discharge
Severity of anxiety	Severity of anxiety measured with the Faces Anxiety Scale (FAS)	Up to three months
Management of sedation	Management of sedation measured by the Richmond Agitation Sedation Scale (RASS)	Until the 5th postoperative day
Management of vigilance	Management of Vigilance measured by Glasgow Coma Scale (GCS)	Until the 5th postoperative day
Management of analgesia and pain levels	Management of analgesia and pain levels measured by Numeric Rating Scale - Visualized (NRS-V), the Faces Pain Scale - Revised (FPS-R), the Behavioral Pain Scale (BPS) or the Behavioral Pain Scale for Non-Intubated (BPS-NI)	Up to three months
Relevant medication		Until the 5th postoperative day
Severity of illness	Severity of illness measured by Sequential Organ Failure Assessment (SOFA-Score), Simplified Acute Physiology Score (SAPS II) and the Acute Physiology and Chronic Health Evaluation (APACHE II)	Up to 14 postoperative days
Mechanical ventilation/weaning failure		Until the 5th postoperative day
Processive Electroencephalography and Electromyography (EEG/EMG) -Data (SedLine®)		At time of surgery
Determination of blood levels	Complete blood count performance (Sysmex®) and acetylcholinesterase-analysis	Change from baseline complete blood count performance (Sysmex®) and acetylcholinesterase-analysis at third postoperative day
Cortisol-analysis		Up to three months
Organ dysfunctions		Up to three months
Infections	Infections according to surgical site infections (SSI) and according to the US Centers for Disease Control and Preventions (CDC).	Up to three months
ICU length of stay		Participants will be followed for the duration of intensive care stay, an expected average of 2 days
Hospital length of stay	Discharge criteria have to be met according to Post Anaesthetic Discharge Scoring System (PADSS) for monitoring patients discharge.	Participants will be followed for the duration of hospital stay, an expected average of 2 weeks
Quality of life	Quality of life is measured by EQ-5D (EuroQol Group), a measure generating a single index value for health status with considerable potential for use in health care evaluation	Up to three months
Incidence of postoperative cognitive dysfunction	Incidence of postoperative cognitive dysfunction (POCD) is measured by Cambridge Neuropsychological Test Automated Battery (CANTAB®) and Mini Mental State Examination (MMSE) including subjective memory feeling (Item 10 of the Geriatric Depression Scale (for already included patients the retrospective follow up by telephone interview)), including limitations in daily activities (EQ-5D)	Up to three months
Mortality		Up to three months
Sleep quality		Up to three months
Photomotor reflex		At time of surgery
Changes of hemodynamic parameters in the intraoperative transesophageal echocardiography	Hemodynamic aparemters are measured in patients for elective CABG surgery	At time of surgery

Collaborators and Investigators

• Sponsor: Claudia Spies
• Investigators: Study Director: Claudia Spies, MD, Prof., Charité-University Medicine (Berlin, Germany)

Publications and helpful links

General Publications

• Singh A, Brenna CTA, Broad J, Kaustov L, Choi S. The Effects of Dexmedetomidine on Perioperative Neurocognitive Outcomes After Cardiac Surgery: A Systematic Review and Meta-analysis of Randomized Controlled Trials. Ann Surg. 2022 May 1;275(5):864-871. doi: 10.1097/SLA.0000000000005196. Epub 2021 Aug 27.

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2014
• Primary Completion (Actual): March 17, 2018
• Study Completion (Actual): July 1, 2018

Study Registration Dates

• First Submitted: March 21, 2014
• First Submitted That Met QC Criteria: March 24, 2014
• First Posted (Estimate): March 26, 2014

Study Record Updates

• Last Update Posted (Actual): September 25, 2019
• Last Update Submitted That Met QC Criteria: September 23, 2019
• Last Verified: September 1, 2019

More Information

Terms related to this study

• Keywords: Neuroprotection
• Additional Relevant MeSH Terms: Mental Disorders; Neurocognitive Disorders; Cognitive Dysfunction; Cognition Disorders; 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; Analgesics, Non-Narcotic; Adrenergic alpha-2 Receptor Agonists; Adrenergic alpha-Agonists; Adrenergic Agonists; Hypnotics and Sedatives; Dexmedetomidine
• Other Study ID Numbers: Neuprodex