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

Study Overview
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Brief Summary
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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.

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

Conditions
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Delirium, Postoperative Cognitive Deficit (POCD)

Intervention / Treatment
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* Drug: Dexmedetomidine (Dexdor®)
* Drug: 0.9% Sodium Chloride


Participation Criteria
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Eligibility Criteria
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Study Group: Inclusion Criteria: Patients aged ≥ 60 years 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 Offered patient information and written consent by the patient (according to German Drug Law § 40 (1) 3b) Premedication only with benzodiazepines Pain therapy during the operation with regional procedures and/or Sufentanil/Fentanyl Anesthesia in cardio surgery according to Heart-Lung-Apparatus Anesthesia with hypnotic agent Propofol Pain therapy after operation according to S3-Guideline Postoperative medication for anxiolysis only with benzodiazepines Exclusion Criteria: Known drug intolerance/allergy: dexmedetomidine or to other ingredients Lacking willingness to save and hand out pseudonymised data within the clinical trial Accommodation in an institution due to an official or judicial order (according to AMG §40 (1) 4) Employee of the Charité - Universitätsmedizin Berlin CVK/CCM Illiteracy Inability to speak and/or read German Minimal mental status examination (MMSE) < 24 Severe hearing loss or visual impairment Acute brain injury Intracranial haemorrhage within one year before participation in the study Manifest psychiatric disease Known illicit substance abuse Acute intoxication For women: Pregnancy or positive pregnancy test within the preoperative screening Homeless or other circumstances, where the patient would not be reachable by telephone or postal services for the 3-months follow up Participation in another interventional clinical trial according to the German Drug Law at time of inclusion and during the trial Acute circulatory failure at time of randomisation (severe hypotension with mean arterial pressure < 55 mmHg despite vasopressors or optimal preload) AV-conduction-block II or III (unless pacemaker installed) Severe bradycardia (heart-rate < 50 bpm, preoperative, permanent) Spinal cord injury with known autonomic dysregulation Preoperative acute cerebrovascular event with neurologic residues Liver insufficiency (Child C cirrhosis, MELD Score > 17) Application of Remifentanil during the operation Deep sedation (RASS, -4 to -5) Administration of Clonidine during administration of the study drug Additional administration of Dexmedetomidine within 3 months after study inclusion Control Group: Inclusion Criteria: Patients aged ≥ 60 years of European descent (Caucasian) Male or female patients with ASA II+III ASA II+III-patients, for which no operation is planned within the next year No operation in the last half year before study inclusion Offered patient information and written informed consent Exclusion Criteria Minimal mental status examination (MMSE) < 24 Missing informed consent for saving and hand out pseudonymous data Neuropsychiatric morbidity, which limits the conduction of the neurocognitive testing Anacusis or Hypoacusis, which limits the conduction of the neurocognitive testing Taking psychothropic drugs (including sleep-inducing drug and benzodiazepine) on a regular basis and other substances, which limit the conduction of the neurocognitive testing

Ages Eligible for Study
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Minimum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Study group<br>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®)<br>* Dexmedetomidine (Dexdor 100 micrograms/ml concentrate for solution for infusion)<br>|
| Placebo Comparator: Control group<br>Application of placebo for a maximum of 48 hours | Drug: 0.9% Sodium Chloride<br>* Solution for infusion: Sodium Chloride : 9.0 g/l; Each ml contains 9 mg sodium chloride mmol/l : Na+ : 154. Cl-: 154.<br>|
| No Intervention: POCD control group<br>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?
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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 |
| --- | --- | --- |
| 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 | 
| Intraoperative cerebral oxymetry |  | At time of surgery | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Neuroprotection