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

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.

Study Overview

• Status: Terminated
• Conditions: Postoperative Delirium (POD); Postoperative Cognitive Deficit (POCD)

• Study Type: Observational
• Enrollment (Actual): 1054

Contacts and Locations

Study Locations

• Germany
  • Berlin, Germany, 13353
    • Department of Anesthesiology and Intensive Care Medicine, CCM and CVK, Charité - Universitätsmedizin Berlin
• Netherlands
  • Utrecht, Netherlands, 3584 CX
    • Department of Intensive Care Medicine, University Medical Center Utrecht

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 65 years and older (Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Surgical patients, 65 years or above (Berlin/Utrecht) ASA I and II patients, 65 years or above (Utrecht) ASA II and III patients, 65 years or above (Berlin/Utrecht)

Description

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

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

4

Cohorts and Interventions

Group / Cohort
Surgical patients - 3 Tesla MRI; 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; 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; 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; 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?

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

Collaborators and Investigators

• Sponsor: Charite University, Berlin, Germany
• Collaborators: European Union
• Investigators: Principal Investigator: Claudia Spies, MD Prof., Department of Anesthesiology and Intensive Care Medicine, CVK/CCM, Charité - University Medicine Berlin; Study Chair: Georg Winterer (BioCog Research Program Coordinator), MD, PhD, Department of Anesthesiology and Intensive Care Medicine, CVK/CCM, Charité - University Medicine Berlin

Publications and helpful links

General Publications

• Ditzel FL, van Montfort SJT, Vernooij LM, Kant IMJ, Aarts E, Spies CD, Hendrikse J, Slooter AJC, van Dellen E; Biomarker Development for Postoperative Cognitive Impairment in the Elderly Consortium. Functional brain network and trail making test changes following major surgery and postoperative delirium: a prospective, multicentre, observational cohort study. Br J Anaesth. 2022 Oct 4. pii: S0007-0912(22)00464-0. doi: 10.1016/j.bja.2022.07.054. [Epub ahead of print]
• Bosancic Z, Spies CD, Muller A, Winterer G, Piper SK, Heinrich M; BioCog Consortium. Association of cholinesterase activities and POD in older adult abdominal surgical patients. BMC Anesthesiol. 2022 Sep 16;22(1):293. doi: 10.1186/s12871-022-01826-y.
• Windmann V, Dreier JP, Major S, Spies C, Lachmann G, Koch S. Increased Direct Current-Electroencephalography Shifts During Induction of Anesthesia in Elderly Patients Developing Postoperative Delirium. Front Aging Neurosci. 2022 Jun 28;14:921139. doi: 10.3389/fnagi.2022.921139. eCollection 2022.
• Fislage M, Feinkohl I, Pischon T, Spies CD, Borchers F, Winterer G, Zacharias N; BioCog Consortium. Presurgical Thalamus Volume in Postoperative Delirium: A Longitudinal Observational Cohort Study in Older Patients. Anesth Analg. 2022 Jul 1;135(1):136-142. doi: 10.1213/ANE.0000000000005987. Epub 2022 Jun 16.
• Heinrich M, Sieg M, Kruppa J, Nurnberg P, Schreier PH, Heilmann-Heimbach S, Hoffmann P, Nothen MM, Janke J, Pischon T, Slooter AJC, Winterer G, Spies CD. Association between genetic variants of the cholinergic system and postoperative delirium and cognitive dysfunction in elderly patients. BMC Med Genomics. 2021 Oct 21;14(1):248. doi: 10.1186/s12920-021-01071-1.
• Koch S, Windmann V, Chakravarty S, Kruppa J, Yürek F, Brown EN, Winterer G, Spies C; BioCog Study Group. Perioperative Electroencephalogram Spectral Dynamics Related to Postoperative Delirium in Older Patients. Anesth Analg. 2021 Dec 1;133(6):1598-1607. doi: 10.1213/ANE.0000000000005668.
• Lichtner G, Zacharias N, Spies CD, Feinkohl I, Winterer G, Pischon T, von Dincklage F; BioCog Consortium. Resting state brain network functional connectivity is not associated with inflammatory markers and blood cell counts in older adults. Clin Neurophysiol. 2021 Jul;132(7):1677-1686. doi: 10.1016/j.clinph.2021.03.042. Epub 2021 May 2.
• Heinrich M, Muller A, Cvijan A, Morgeli R, Kruppa J, Winterer G, Slooter AJC, Spies CD; BioCog Consortium. Preoperative Comparison of Three Anticholinergic Drug Scales in Older Adult Patients and Development of Postoperative Delirium: A Prospective Observational Study. Drugs Aging. 2021 Apr;38(4):347-354. doi: 10.1007/s40266-021-00839-5. Epub 2021 Mar 15.
• Kant IMJ, de Bresser J, van Montfort SJT, Mutsaerts HJMM, Witkamp TD, Buijsrogge M, Spies C, Hendrikse J, Slooter AJC. Preoperative brain MRI features and occurrence of postoperative delirium. J Psychosom Res. 2021 Jan;140:110301. doi: 10.1016/j.jpsychores.2020.110301. Epub 2020 Nov 16.
• Deffland M, Spies C, Weiss B, Keller N, Jenny M, Kruppa J, Balzer F. Effects of pain, sedation and delirium monitoring on clinical and economic outcome: A retrospective study. PLoS One. 2020 Sep 2;15(9):e0234801. doi: 10.1371/journal.pone.0234801. eCollection 2020.
• van Montfort SJT, van Dellen E, Wattel LL, Kant IMJ, Numan T, Stam CJ, Slooter AJC. Predisposition for delirium and EEG characteristics. Clin Neurophysiol. 2020 May;131(5):1051-1058. doi: 10.1016/j.clinph.2020.01.023. Epub 2020 Feb 21.
• Feinkohl I, Borchers F, Burkhardt S, Krampe H, Kraft A, Speidel S, Kant IMJ, van Montfort SJT, Aarts E, Kruppa J, Slooter A, Winterer G, Pischon T, Spies C. Stability of neuropsychological test performance in older adults serving as normative controls for a study on postoperative cognitive dysfunction. BMC Res Notes. 2020 Feb 4;13(1):55. doi: 10.1186/s13104-020-4919-3.
• Kant IMJ, Mutsaerts HJMM, van Montfort SJT, Jaarsma-Coes MG, Witkamp TD, Winterer G, Spies CD, Hendrikse J, Slooter AJC, de Bresser J; BioCog Consortium. The association between frailty and MRI features of cerebral small vessel disease. Sci Rep. 2019 Aug 5;9(1):11343. doi: 10.1038/s41598-019-47731-2.
• Windmann V, Spies C, Brown EN, Kishnan D, Lichtner G, Koch S; BioCog Study Group. Influence of midazolam premedication on intraoperative EEG signatures in elderly patients. Clin Neurophysiol. 2019 Sep;130(9):1673-1681. doi: 10.1016/j.clinph.2019.05.035. Epub 2019 Jul 10.
• Lachmann G, Kant I, Lammers F, Windmann V, Spies C, Speidel S, Borchers F, Hadzidiakos D, Hendrikse J, Winterer G, de Bresser J; BIOCOG Consortium. Cerebral microbleeds are not associated with postoperative delirium and postoperative cognitive dysfunction in older individuals. PLoS One. 2019 Jun 14;14(6):e0218411. doi: 10.1371/journal.pone.0218411. eCollection 2019.
• Feinkohl I, Janke J, Hadzidiakos D, Slooter A, Winterer G, Spies C, Pischon T. Associations of the metabolic syndrome and its components with cognitive impairment in older adults. BMC Geriatr. 2019 Mar 7;19(1):77. doi: 10.1186/s12877-019-1073-7.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2014
• Primary Completion (Actual): December 1, 2017
• Study Completion (Actual): June 1, 2019

Study Registration Dates

• First Submitted: September 23, 2014
• First Submitted That Met QC Criteria: October 14, 2014
• First Posted (Estimate): October 15, 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

• Additional Relevant MeSH Terms: Mental Disorders; Neurocognitive Disorders; Cognitive Dysfunction; Cognition Disorders
• Other Study ID Numbers: BioCog