Biomarker Development for Postoperative Cognitive Impairment in the Elderly (BioCog)

Study Overview
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Brief Summary
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The research leading consortium to these results has received funding from the European Union Seventh Framework Programme [FP7/2007-2013] under grant agreement no 602461 (www.biocog.eu). The investigators will establish valid biomarkers panels (neuroimaging and molecular) for risk and clinical outcome prediction of postoperative delirium (POD)/postoperative cognitive deficit (POCD) in elective surgical patients (Age ≥ 65 years) in study centers in Berlin,Germany (data collection within 2 years after initial hospital stay) and Utrecht, The Netherlands (data collection within 1 year after initial hospital stay), thereof cerebrospinal fluid (only once on day of surgery in patients with planned spinal anesthesia/combined spinal epidural analgesia in patients, only in Berlin). A control group of 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. The ASA II/III- control patients receive additionally MRI-scan (3 Tesla) at baseline, after 3 months and after 1 (Utrecht) and 2 years (Berlin). To analyze scanner variability we additionally measure at maximum 20 subjects (Age ≥ 65 years, ASA I and II) from Utrecht in the MRI scanner (3-Tesla) in Berlin and vice versa. A study group at maximum (n= 80) and is collected for measuring 7 Tesla MRI at two timepoints (Baseline and 90 days).The primary endponit of this substudy is gamma amino-butyric acid concentration in CNS after 3-months (measured by MRI). A retrospective comparison group (extracting 8000 intensive care unit patient data from the patient data management system during the BioCog study period in 2016) to analyse economic effects that are caused by the implementation of quality indicators in health care. An interim-analysis is performed on the primary endpoint after 400 included patients. The resulting (multivariate) expert system is expected: 1) to support clinical decision-making in patient care, e.g. to balance the individual POD/POCD risk against the expected overall clinical outcome of an (elective) surgical intervention, 2) to allow the design of more sophisticated and hypothesis-driven clinical studies and drug trials (translational research) in the future. The latter will be possible on the basis of biomarker-based sub-grouping of patients and a better understanding of relevant pathophysiological processes. Furthermore, a state-of-the art clinical database and biobank will be created that does not yet exist worldwide. Both the expert system and the reference database/biobank will expand the leadership of the contributing academic institutions in this particular research area. In addition, the newly created biobank will become an integral part of the European Biobanking and Biomolecular Resources Research Infrastructure (BBMRI) which allows top address specific and hypothesis-driven research questions. Most notably, the developed (multivariate) expert system also has the potential for commercialization. Possible customers are: 1) physicians and hospital departments being involved in pre-surgical decision making, 2) pharmaceutical industry intending to conduct biomarker-based drug trials in POD/POCD.

Official Title
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Biomarker Development for Postoperative Cognitive Impairment in the Elderly (BioCog)

Conditions
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Postoperative Delirium (POD), Postoperative Cognitive Deficit (POCD)

Participation Criteria
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Eligibility Criteria
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Study Group (Berlin/Utrecht): Inclusion Criteria: Male and female patients aged ≥ 65 years, of European descent (Caucasian) Elective surgery with an expected operative time ≥ 60 minutes Ability to give informed consent after receiving spoken and written information of the study Eligibility for magnetic resonance Imaging Exclusion Criteria: Mini-Mental-State-Examination ≤ 23 points Homelessness or other circumstances where the patient would not be reachable by phone or postal services during follow-up. Participation in another prospective interventional clinical study during participation in this clinical study during hospital stay Accommodation in an institution due to an official or judicial order 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 Intraoperative clectroencephalography - examinations (Study Group Berlin): Exclusion criteria: Neurological preconditions Proposed neurological surgery Control Group (Berlin/Utrecht): Inclusion criteria: Male and female patients aged ≥ 65 years, of European descent (Caucasian) ASA II and III patients No operation in the last half year before study inclusion Eligibility for magnetic resonance Imaging Exclusion Criteria: Mini-Mental-State-Examination ≤ 23 Points 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 substances, which limit the conduction of the neurocognitive testing Control Group (Utrecht) - Scannervariability: Inclusion criteria: Male and female patients aged ≥ 65 years, of European descent (Caucasian) ASA I and II patients No operation in the last half year before study inclusion Eligibility for magnetic resonance Imaging Study Group (Berlin) - 7 Tesla MRI: Criteria as of the 3-Tesla- study group and additionally: Exclusion criteria: absolute 7 - Tesla MRI-contraindications relative 7 - Tesla MRI-contraindications

Ages Eligible for Study
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Minimum Age: 65 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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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Surgical patients - 3 Tesla MRI<br>A study group of at maximum n= 1200 is collected for measuring 3 Tesla MRI at two timepoints (Baseline and 90 days) in Berlin/Utrecht. They include surgical procedures within body cavity e.g. abdomen or thorax from departments of general surgery, urology, gynecology or thoracic surgery; orthopaedic operations (hip-, knee-, endoprosthesis or spine (including neurosurgical spine operations)); cardiac surgery and operation of extracranial/intracranial head and neck Data collection from study center Utrecht ist within one year after initial hospital stay. Data collection from study center Berlin is within two years after initial hospital stay. | |
| Patients ASA II/III - 3 Tesla MRI<br>A control group of at maximum n= 300 ASA II/III- patients is collected for measuring the learning experience during the cognitive testings. They are matched on age, education, and gender to the study patients. The 104 ASA II/III- patients should receive additionally MRI-scan (3 Tesla) at baseline, after 3 months and after 1 year in Utrecht, after 3 months, after 1, 2 years in Berlin. Data collection from study center Utrecht ist within one year after initial hospital stay. Data collection from study center Berlin is within five years after initial hospital stay. | |
| Volunteers ASA I/II - 3 Tesla MRI<br>To analyze scanner variability we additionally measure at maximum 20 subjects (Age ≥ 65 years) from Utrecht in the MRI scanner (3-Tesla) in Berlin and vice versa. | |
| Surgical patients - 7 Tesla MRI<br>A study Group of at maximum n= 80 should be collected for measuring 7 Tesla MRI at two timepoints (Baseline and 90 days) in Berlin. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Delirium | Postoperative delirium rate, defined according to Diagnostic and Statistical Manual of Mental Disorders (DSM-V) and/or as ≥ 2 cumulative points in the nursing Delirium Screening Scale (Nu-DESC) and/or a positive Confusion Assessment Method (CAM) and/or Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) score and/or patient chart review that shows descriptions of delirium. | Participants will be followed for the duration of hospital stay, an expected average of 7 days | 
| Incidence of postoperative cognitive deficit (POCD) | POCD will be measured by a defined Cambridge Neuropsychological Test Automated Battery (CANTAB) POCD will be measured by a defined Cambridge Neuropsychological Test Automated Battery (CANTAB) and paper pencil tests (TMT A und B, Grooved Pegboard) and the Mini - Mental State Examination (MMSE) | Up to 3 months after the operation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Delirium | Diagnostic and Statistical Manual of Mental Disorders (DSM-V) Nursing Delirium Screening Scale (Nu-DESC) Intensive Care Delirium Screening Checklist (ICDSC) Delirium Detection Scale (DDS) Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) Confusion Assessment Method (CAM) Chart Review | Participants will be followed for the duration of hospital stay, an exspected average of 7 days | 
| Duration of subsyndromal postoperative delirium | Nu-DESC score 1 and/or any criteria suggestive of POD (as described under Primary Outcome Measures) that do not fulfill DSM-5 criteria for delirium. | Participants will be followed for the duration of hospital stay, an exspected average of 7 days | 
| Incidence of subsyndromal postoperative delirium | Nu-DESC score 1 and/or any criteria suggestive of POD (as described under Primary Outcome Measures) that do not fulfill DSM-5 criteria for Delirium | Participants will be followed for the duration of hospital stay, an exspected average of 7 days | 
| Intensive care unit length of stay |  | Participants will be followed for the duration of intensive care unit stay, an expected average of 5 days | 
| Hospital length of stay |  | Participants will be followed for the duration of hospital stay, an exspected average of 7 days | 
| Postoperative organ complications | Postoperative organ complications are classified according to Clavien - Dindo classification. | Participants will be followed for the duration of hospital stay, an exspected average of 7 days | 
| Incidence of postoperative cognitive deficit | POCD will be measured by a defined Cambridge Neuropsychological Test Automated Battery (CANTAB), paper pencil tests (TMT A und B, Grooved Pegboard) and the Mini - Mental State Examination (MMSE) | 1 year, 2 years, 5 years after the operation | 
| Socioeconomic characteristics | Study center Berlin: Health economic data according to cost of patient care (The §21 dataset (diagnoses and operation-codes). Hospital costs are calculated according to the Institute for the Hospital Remuneration System (InEK) calculation scheme to compare the refinanced costs in each cost category/cost-center segment from study center Charité. Necessity and indirect costs of medical care (outpatient visits) after hospital stay. | 3 months, 1, 2 and 5 years after the operation | 
| Health related quality of life | Study center Berlin: Measurement by EQ-5D | 3 months, 1, 2 and 5 years after the operation | 
| Barthel Index |  | 3 months, 1, 2 and 5 years after the operation | 
| Instrumental activities of daily living scale |  | 3 months, 1, 2 and 5 years after the operation | 
| Hand grip strength test |  | 3 months, 1, 2 and 5 years after the operation | 
| Malnutrition | Mini Nutritional Assessment - Short form, Serum albumin | 3 months, 1, 2 and 5 years after the operation | 
| Mobility | Timed up and go test | 3 months, 1, 2 and 5 years after the operation | 
| Neuroimaging Biomarker |  | 3 months, 1, 2 and 5 years after the operation | 
| Molecular Biomarker |  | 3 months | 
| Health related Quality of life | Study center Utrecht: Measurement by EQ-5D | 3 months, 1 year after the operation | 
| Socioeconomic characteristics | Study center Utrecht: Health economic data according to direct cost of patient care (inpatient and outpatient stays) and necessity and indirect costs of medical care (outpatient visits) after hospital stay. | 3 months, 1 year after the operation | 
| Heart rate variability |  | Study center Berlin: Participants will be followed for the duration of hospital stay, an exspected average of 7 days | 
| Light Levels (lux) |  | Study center Berlin: Participants will be followed for the duration of hospital stay, an exspected average of 7 days | 
| Light frequencies |  | Study center Berlin: Participants will be followed for the duration of hospital stay, an exspected average of 7 days | 
| Depression | Hospital Anxiety and Depression Scale (HADS) (Study Center Utrecht), GDS-15 (Study Center Berlin) | Participants will be followed for the duration of hospital stay, an exspected average of 7 days | 
| Anxiety | Faces Anxiety Scale (FAS) | Participants will be followed for the duration of hospital stay, an exspected average of 7 days | 
| Electroencephalography (EEG)- Mapping | Study center Berlin: EEG with19 electrodes and hypo- and hyperventilation in physiological limits (no patients with neurological pre-existing conditions or proposed neuro-surgery) | At time of surgery | 
| Mortality |  | 3 months, 1, 2 and 5 years after the operation | 
| Depth of consciousness index | Depth of consciousness index measured by processive Electroencephalography and Electromyography (EEG/EMG) -Data (SedLine®) | At time of surgery | 
| Intraoperative cerebral oxymetry |  | At time of surgery | 
| Changes of Electroencephalography | Signals are measured by EEG Monitor and Delir Monitor software | Participants will be followed up until the end of postanesthesia care unit, an exspected average of 2 days | 
| Depth of sedation | Intraoperatively: Observe´s Assessment of Alertness/Sedation scale (OAA/S) and postoperatievly: Richmond Agitation Sedation Scale (RASS) | At time of surgery and Participants will be followed for the duration of intensive care unit stay, an expected average of 5 days | 
| Pain Scales | Perioperatively: Pain sensitivity questionnare; Pain Catastrophing Scale (PCS-GE)(PSQ); Numerische Rating Scale (NRS-V); Behavioural Pain Scale (BPS for ventilated) and BPS-NI (for non-ventilated) patients, Critical-Care Pain Observation Tool (CPOT); Rotterdam Elderly Pain Observation Scale (REPOS); Pupillometry by Neurolight; Intraoperatively: Measurement of the nociceptive flexion reflex threshold (Dolosys Paintracker); Measurement of the pupillary dilation reflex threshold (AlgiScan); Automatic collection of the data of the medication pumps; Multiple blood analysis to measure the plasma-concentrations of anesthetics; Automatic collection of the data of the SED-Line-EEG-Monitor. | 3 months | 
| Quality indicators of intensive care unit | Study Center Berlin: This endpoint aims to analyse economic effects of the prospective study patients and retrospective control subjects in the intensive care unit that are caused by the implementation of quality indicators in health care. | Participants will be followed for the duration of intensive care unit stay, an expected average of 5 days | 
| Glucosevariability | Measured by Continuous Glucose Monitoring System | At time of surgery and Participants will be followed for the duration of intensive care unit stay, an expected average of 5 days | 
| Frailty |  | 3 months, 1, 2 and 5 years after the operation | 
| Coagulationdisorder of the blood | Kidney marker | 3 months |