Clinical trial NCT02265263: Biomarker Development for Postoperative Cognitive Impairment in the Elderly (BioCog)
Official title: Biomarker Development for Postoperative Cognitive Impairment in the Elderly (BioCog)
Study type: OBSERVATIONAL
Overall status: TERMINATED
Conditions: Postoperative Delirium (POD)
Postoperative Cognitive Deficit (POCD)
Lead sponsor: Charite University, Berlin, Germany
Sponsor class: OTHER
Collaborators: name: European Union
First posted: 2014-10-15
Enrollment: 1054
Sex: ALL
Minimum age (years): 65
Standard ages: OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
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)

Brief summary: 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.


Eligibility criteria: 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

Primary outcomes:
measure: Incidence of Delirium
timeFrame: Participants will be followed for the duration of hospital stay, an expected average of 7 days
measure: Incidence of postoperative cognitive deficit (POCD)
timeFrame: Up to 3 months after the operation
Secondary outcomes:
measure: Duration of Delirium
timeFrame: Participants will be followed for the duration of hospital stay, an exspected average of 7 days
measure: Duration of subsyndromal postoperative delirium
timeFrame: Participants will be followed for the duration of hospital stay, an exspected average of 7 days
measure: Incidence of subsyndromal postoperative delirium
timeFrame: Participants will be followed for the duration of hospital stay, an exspected average of 7 days
measure: Intensive care unit length of stay
timeFrame: Participants will be followed for the duration of intensive care unit stay, an expected average of 5 days
measure: Hospital length of stay
timeFrame: Participants will be followed for the duration of hospital stay, an exspected average of 7 days
measure: Postoperative organ complications
timeFrame: Participants will be followed for the duration of hospital stay, an exspected average of 7 days
measure: Incidence of postoperative cognitive deficit
timeFrame: 1 year, 2 years, 5 years after the operation
measure: Socioeconomic characteristics
timeFrame: 3 months, 1, 2 and 5 years after the operation
measure: Health related quality of life
timeFrame: 3 months, 1, 2 and 5 years after the operation
measure: Barthel Index
timeFrame: 3 months, 1, 2 and 5 years after the operation
measure: Instrumental activities of daily living scale
timeFrame: 3 months, 1, 2 and 5 years after the operation
measure: Hand grip strength test
timeFrame: 3 months, 1, 2 and 5 years after the operation
measure: Malnutrition
timeFrame: 3 months, 1, 2 and 5 years after the operation
measure: Mobility
timeFrame: 3 months, 1, 2 and 5 years after the operation
measure: Neuroimaging Biomarker
timeFrame: 3 months, 1, 2 and 5 years after the operation
measure: Molecular Biomarker
timeFrame: 3 months
measure: Health related Quality of life
timeFrame: 3 months, 1 year after the operation
measure: Socioeconomic characteristics
timeFrame: 3 months, 1 year after the operation
measure: Heart rate variability
timeFrame: Study center Berlin: Participants will be followed for the duration of hospital stay, an exspected average of 7 days
measure: Light Levels (lux)
timeFrame: Study center Berlin: Participants will be followed for the duration of hospital stay, an exspected average of 7 days
measure: Light frequencies
timeFrame: Study center Berlin: Participants will be followed for the duration of hospital stay, an exspected average of 7 days
measure: Depression
timeFrame: Participants will be followed for the duration of hospital stay, an exspected average of 7 days
measure: Anxiety
timeFrame: Participants will be followed for the duration of hospital stay, an exspected average of 7 days
measure: Electroencephalography (EEG)- Mapping
timeFrame: At time of surgery
measure: Mortality
timeFrame: 3 months, 1, 2 and 5 years after the operation
measure: Depth of consciousness index
timeFrame: At time of surgery
measure: Intraoperative cerebral oxymetry
timeFrame: At time of surgery
measure: Changes of Electroencephalography
timeFrame: Participants will be followed up until the end of postanesthesia care unit, an exspected average of 2 days
measure: Depth of sedation
timeFrame: At time of surgery and Participants will be followed for the duration of intensive care unit stay, an expected average of 5 days
measure: Pain Scales
timeFrame: 3 months
measure: Quality indicators of intensive care unit
timeFrame: Participants will be followed for the duration of intensive care unit stay, an expected average of 5 days
measure: Glucosevariability
timeFrame: At time of surgery and Participants will be followed for the duration of intensive care unit stay, an expected average of 5 days
measure: Frailty
timeFrame: 3 months, 1, 2 and 5 years after the operation
measure: Coagulationdisorder of the blood
timeFrame: 3 months
Other outcomes:
Locations:
city: Berlin
country: Germany
facility: Department of Anesthesiology and Intensive Care Medicine, CCM and CVK, Charité - Universitätsmedizin Berlin
city: Utrecht
country: Netherlands
facility: Department of Intensive Care Medicine, University Medical Center Utrecht
Study officials:
affiliation: Department of Anesthesiology and Intensive Care Medicine, CVK/CCM, Charité - University Medicine Berlin
name: Claudia Spies, MD Prof.
role: PRINCIPAL_INVESTIGATOR
affiliation: Department of Anesthesiology and Intensive Care Medicine, CVK/CCM, Charité - University Medicine Berlin
name: Georg Winterer (BioCog Research Program Coordinator), MD, PhD
role: STUDY_CHAIR
References:
citation: 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. 2023 Feb;130(2):e281-e288. doi: 10.1016/j.bja.2022.07.054. Epub 2022 Oct 17.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: Koch S, Windmann V, Chakravarty S, Kruppa J, Yurek 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.