Analysis of Frailty Syndrome Within the Framework of the Innovation Fund Project PRÄP-GO (ANA-PRÄP-GO)

Study Overview
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Brief Summary
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The patients included in PRÄP-GO and the corresponding comparison cohorts will be offered to participate in this complementary study in order to be able to carry out a detailed characterization and phenotyping of the frailty complex.

Detailed Description
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As part of the innovation fund project PRÄP-GO (EA1/225/19), a multimodal intervention is being conducted in patients with a frailty syndrome. However, the health care research project is limited to evaluating clinical issues only. In order to be able to research further pathophysiological, clinical, psychosocial and work-organizational connections, different groups of participants will be offered the participation in this scientific support program of PRÄP-GO. The groups of participants in this accompanying program ANA-PRÄP-GO are: Randomized study patients with a frailty syndrome of the intervention study PRÄP-GO (PG cohort) Non-frail surgical control group (NFC cohort) Non-surgical comparison group (NO cohort) Participants with health professions (GB cohort) Additionally, relatives of the patients can be included. Subprojects are included to reflect research questions of interest in sub groups: Success of endoprosthetic implants (clinical outcome and gait pattern after total hip arthroplasty and total knee arthroplasty in frail patients) Functional treatment outcome and health-related quality of life after elective spinal surgery in the PG cohort, in the NFC cohort, and in the NO cohort Hemodynamic evaluation in patients of the PG and NFC cohort with preoperative abnormal cardiovascular function Establishment of a German standard database for 14 CANTAB tests by CANTAB Connect technology Aggregated evaluation of the cognitive data of different surgical cohorts from studies carried out at the department of anesthesiology to describe domain-specific changes in the perioperative course Perspectives of different health professional groups regarding barriers and facilitators in the implementation of a prehabilitation program and necessary changes in skill, organizational and management, and communication in an interdisciplinary setting Perspectives of patients and significant others regarding the organizational pathway of the prehabilitation program Frequency, pathophysiology and trajectory of muscle weakness as well as functional impairments of patients admitted to intensive care units of the PG and NFC cohort and their long-term outcomes. The gut microbiome as a potential risk factor for perioperative neurocognitive disorders (PNDs) in the elderly Evaluation of nutrition data in all cohorts (e.g. adherence to mediterranean diet, nutrition habits, nutritional status, dental status etc.)

Official Title
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Analysis of the Pathophysiology of Frailty Syndrome and Clinical Development of Frailty Within the Framework of the Innovation Fund Project PRÄP-GO (ANA-PRÄP-GO)

Conditions
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Frailty Syndrome

Intervention / Treatment
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* Behavioral: Prehabilitation- new form of care


Participation Criteria
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Eligibility Criteria
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PG cohort: Inclusion criteria Consent given and inclusion in PRÄP-GO Patient capable of giving consent or existing legal guardian in the case of patients not capable of giving consent Exclusion criteria - None NFC cohort: Inclusion criteria Patient capable of giving consent or existing legal guardian in the case of patients not capable of giving consent Age ≥ 70 years Elective surgery planned Expected anesthesia duration> 60 min No frailty syndrome (0 positive out of 5 standardized parameters) according to the physical frailty phenotype (Fried et al., 2001) Exclusion criteria Severe cardiac or pulmonary disease (NYHA IV, Gold IV) Intracranial interventions Moribund patients (palliative situation) Patients with a neuropsychiatric clinical picture or severe hearing and / or visual acuity impairment (not compensated by visual or hearing aids), which limit the performance of the neurocognitive tests Insufficient language skills Participation in another interventional rehabilitation study or a study according to the German Drug Law or the medical Device Law that has not been approved by the study leader (Exception: parallel participation in adjuvant therapy study). NO cohort: Inclusion criteria - Age ≥ 70 years No elective surgery planned No surgery within 6 months prior to study enrollment Exclusion criteria - See NFC cohort GB cohort: Inclusion criterion - Doctor, nurse or therapist from the cooperation partners of PRAEP-GO who were involved in the project Exclusion criterion - Language barrier Relatives: Inclusion criteria Member of a patient in the PRÄP-GO cohort Age ≥ 18 years Exclusion criterion - Language barrier

Ages Eligible for Study
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Minimum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| PG cohort<br>800 randomized surgical study patients with a frailty syndrome (Pre-frail and frail) of the intervention study PRÄP-GO (PG cohort). 400 study patients receive the intervention and 400 study patients receive standard of care. | Behavioral: Prehabilitation- new form of care<br>* The participants in the intervention group take part in a shared decision-making (SDM) conference to plan the intervention. The therapeutic content of the prehabilitation is defined individually for each patient in the SDM conference. Prehabilitation will be a structured and individually tailored 3-week program.<br>|
| NFC cohort<br>400 non-frail surgical control group (NFC cohort) | |
| NO cohort<br>300 non-operative control group (NO cohort) | |
| GB cohort<br>Skill-Change-Management: a maximum of 30 coworkers and analysis of guiding principle: to a maximum of 35 patients, 30 relatives and 45 coworkers | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frailty | Frequency of frailty is measured by modified Fried criteria (category 1 +2 = pre-frail, category 3 -5 = frail) | Up to 1 year | 
| Neuro-cognitive disorder (NCD) | Frequency of neuro-cognitive disorder (mild / major NCD) | Up to 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of delirium | Incidence of delirium, defined according to Diagnostic and Statistical Manual of Mental Disorders (DSM-V), Richmond Agitation Scale (RASS), Nursing Delirium Screening Scale (Nu-DESC), Confusion Assessment Method (CAM), Confusion Assessment Method for the Intensive Care Unit (CAM-ICU), along with the delirium severity scores Confusion Assessment Method Severity-Score (CAM-S) in English, Intensive Care Delirium Screening Checklist (ICDSC), Delirium Rating Scale Revised 98 (DRS-R-98) in English and patient chart review. The assessment period is from the recovery room up to five postoperative days or until hospital discharge. | During the hospital stay, an expected average of 1 week | 
| Severity of delirium | Severity of delirium defined as a composite score based on: Confusion Assessment Method Severity-Score(CAM-S); Confusion Assessment Method (CAM), Confusion Assessment Method for the Intensive Care Unit (CAM-ICU), Delirium Rating Scale Revised (DSR-R-98) in English, Intensive Care Delirium Screening Checklist (ICDSC) and Nursing Delirium Screening Scale (Nu-DESC) and patient chart review. | During the hospital stay, an expected average of 1 week | 
| Nursing Delirium Screening Scale (Nu-DESC) | Nursing Delirium Screening Scale (Nu-DESC) score of ≥ 2 is indicative of delirium, range: 0-10 points, 10 = most severe. | During the hospital stay, an expected average of 1 week | 
| Confusion Assessment Method (CAM) | Confusion Assessment Method (CAM) score is indicative of delirium, if the items 1 and 2 and 3 or the items 1 and 2 and 4 are measured positively. | During the hospital stay, an expected average of 1 week | 
| Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) | Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) score is indicative of delirium, if the items 1 and 2 and 3 or the items 1 and 2 and 4 are measured positively. | During the hospital stay, an expected average of 1 week | 
| Confusion Assessment Method Severity-Score (CAM-S Long Form) in English | The Confusion Assessment Method Severity-Score (CAM-S Long Form) is an 10-item delirium screening instrument (range: 0-19 points, 19 = most severe). | During the hospital stay, an expected average of 1 week | 
| Intensive Care Delirium Screening Checklist (ICDSC) | The ICDSC is an 8-item delirium screening instrument (range: 0-8 points). The score is indicative of delirium, if the item is > 3. | During the hospital stay, an expected average of 1 week | 
| Delirium Rating Scale Revised 98 in English (DRS-R-98) | The delirium rating scale revised 98 is a delirium screening instrument (range 0-46). The score is indicative of delirium, if the item is > 14.5. | During the hospital stay, an expected average of 1 week | 
| Delirium Severity Scale (CAM-ICU-7) in English | A 7-point rating scale (0-7) was derived from the CAM-ICU and RASS assessments 0-2: no delirium, 3-5: mild to moderate delirium, and 6-7: severe delirium. | During the hospital stay, an expected average of 1 week | 
| Number of Participants with Delirium as Determined by Chart Review | Delirium is identified chart-based. | During the hospital stay, an expected average of 1 week | 
| Delirium days | The duration of delirium is measured in days. | During the hospital stay, an expected average of 1 week | 
| COVID-19 | SARS-CoV-2 infection | Up to 1 year | 
| Cardiovascular function 1 | Cardiovascular function is measured by Transesophageal Echocardiography. | Up to 1 year | 
| Cardiovascular function 2 | Cardiovascular function is measured by cardiovascular complications. | Up to 1 year | 
| Ethical aspects | Wishes of the patient about the intensity of therapy and therapy goals are measured with a questionnaire. | Up to 1 year | 
| Patient satisfaction | Patient satisfaction score is measured with a likert scale (0 - 10) | Up to 1 year | 
| Patient-related outcome measures (PROMS) | Different tools and questionnaires are combined to measure Patient-related outcome. | Up to 1 year | 
| Patient-related experience measures (PREMS) | Patient-reported experiences of health care are measured with a questionnaire. | Up to 1 year | 
| incidence of dementia | incidence of dementia is measured by MOCA | Up to 1 year | 
| incidence of cognitive impairment | incidence of cognitive impairment is measured by a validated score. | Up to 1 year | 
| Findings of Memory consultation | During memory consultation cognitive diagnostic findings are measured. | Up to 1 year | 
| Stress | Stress is measured by Perceived Stress Questionnaire (PSQ20), which ranges from 20-80 points | Up to 1 year | 
| Anxiety 1 | Anxiety is measured by Generalized Anxiety Disorder 7, points range from 0-21 | Up to 1 year | 
| Anxiety 2 | Anxiety 2 is measured by Faces Anxiety Scale, a valid single-item for self-report measure of state | Up to 1 year | 
| Insomnia | Insomnia is measured by Insomnia Severity Index (ISI), which ranges from 0- 21 points | Up to 1 year | 
| Neuroimaging | Routine neuroimaging results were planned to be documented in the hospital including all techniques to image the nervous system as ultrasound, magnetic resonance imaging, conventional radiography, computed tomography and positron emission tomography. | Up to 1 year | 
| Demand of health services | The need of treatment for curing an illness. | Up to 1 year | 
| Adverse events | Adverse events are measured in all participants, who receive study measurements | Up to 1 year | 
| Mini Nutritional Assessment-Short | Nutritional Status is measured using Mini Nutritional Assessment-Short-form (MNA-SF) | Up to 1 year | 
| Adherence to Mediterranean diet (MD) | Adherence to Mediterranean diet (MD) is measured with a German Medi-Score, could range from 0 to 9, with higher scores (6-9) indicating greater MD adherence. | Up to 1 year | 
| Sarcopenia | The composite outcome measure Sarcopenia is defined by the following three criteria: 1) low muscle strength (hand grip strength), 2) low muscle quantity (calf circumference and 3) low physical performance (gait speed). Criterion (1) identifies probable sarcopenia, additional documentation of criterion (2) confirms sarcopenia diagnosis, and if all criteria (1), (2) and (3) are met, sarcopenia is considered severe. | Up to 1 year | 
| Calf circumference | Calf circumference is measured in a standardized position and documented in centimeter. | Up to 1 year | 
| Arm circumference | Arm circumference is measured in a standardized position and documented in centimeter. | Up to 1 year | 
| Dental status | (number of teeth, Oral Health Assessment Tool (OHAT), Geriatric Oral Health Assessment Index (GO-HAI), questions regarding prothesis, dentist visits and dental care) | Up to 1 year | 
| Quality of life | Quality of life is measured by Care Related Quality of Life (CarerQoL) | Up to 1 year | 
| Postoperative complications | Complications are measured according to the Clavien-Dindo classification | Up to 30 days | 
| Psychometric properties of the Meta Memory questionnaire | Psychometric properties of the Meta Memory questionnaire are measured twice before surgery. | During the hospital stay, at the beginning of the investigation, an average of two hours. | 
| Number of participants with changes in laboratory values 1 | Routine laboratory results were planned to be documented in the hospital including hemoglobin, lymphocytes, total neutrophils, platelet count and white blood cell (WBC) count from blood samples. | Up to 1 year | 
| Number of participants with changes in laboratory values 2 | Routine laboratory results were planned to be documented from the general practitioner including hemoglobin, lymphocytes, total neutrophils, platelet count and white blood cell (WBC) count from blood samples. | Up to 1 year | 
| APOE polymorphisms | APOE polymorphisms are measured from whole blood once during hospital stay, an expected average of one week. | Up to 1 year | 
| Total interleukin-8 | Total interleukin-8 is measured from whole blood | Up to 1 year | 
| Cholinesterases 1 | Acetylcholinesterase and Butyrylcholinesterase are measured from liquor | Up to 1 year | 
| Cholinesterases 2 | Acetylcholinesterase and Butyrylcholinesterase are measured from whole blood | Up to 1 year | 
| Intracellular pH | Intracellular pH is measured from whole blood. | Up to 1 year | 
| Autophagy of platelets | Autophagy of platelets is measured from whole blood. | Up to 1 year | 
| Peripheral Blood Mononuclear Cell | Peripheral Blood Mononuclear Cell are measured from whole blood. | Up to 1 year | 
| Multiplex gene expression analyzes (neuroinflammation and micro RNA panels) | Multiplex gene expression analyzes (neuroinflammation and micro RNA panels) are measured from whole blood | Up to 1 year | 
| Autoantibodies | Autoantibodies against beta2-adrenergic receptor, muscarinic acetylcholine receptor (M3 / M4), serotonin receptor, dopamine receptor are measured from serum | Up to 1 year | 
| Trypotophan metabolites and short-chain fatty acids | Trypotophan metabolites and short-chain fatty acids are measured from serum with metabolomic analysis | Up to 1 year | 
| Biomarker panel | Biomarker are measured from serum by metabolomic analyses to characterize the frailty complex. | Up to 1 year | 
| Cytokines | Cytokines (IFN-Ɣ IL-1β IL-4 IL-6 IL-10 IL-17A IL-17E IL-17F IL-21 IL-23 TGF-β1) are measured from plasma | Up to 1 year | 
| Chemokines | Chemokines (CCL2 (MCP-1) CCL3 CCL4 CCL5 (RAN-TES) CCL11 (Eotaxin) CCL19 CCL20 CXCL1 CXCL8 (IL-8) CXCL10 (IP-10) CXCL12 (SDF1A) are measured from plasma | Up to 1 year | 
| Markers immune-brain axis and gut-brain axis | Markers immune-brain axis and gut-brain axis (zonulin, endothelial cell-specific molecule 1, S100A6, S100A8, S100A9, S100P, S100beta, Interleu-kin-16, CD162, BDNF, CD272, p-selectin, be-ta2microglobulin , Haptoglobin, cathelicidin, NCAM-1, BTLA and CXCR5) are measured from plasma | Up to 1 year | 
| Protein panel | Proteins are measured from plasma by proteome analysis. | Up to 1 year | 
| Microbiome 1 | Analyzes of bacteria-specific 16S DNA from different biomaterial. | Up to 1 year | 
| Microbiome 2 | Analyzes of sequences of known microorganisms from different biomaterial. | Up to 1 year | 
| Serum albumin | Serum albumin is measured from whole blood | Up to 1 year | 
| HbA1c | HbA1c is measured from whole blood | Up to 1 year | 
| Vitamin D (cholecalciferol) | Vitamin D is measured from whole blood | Up to 1 year | 
| Dementia markers | Dementia markers: beta amyloid 1-40, beta-amyloid 1-42, beta-amyloid ratio (42/40 * 10), phospho-TAU, protein 14-3-3, PRPSc, TAU (total tau) are measured from liquor | Up to 1 year | 
| Analysis of microbiome | Microbial diversity is measured from blood, urine and feces (e.g. Shannon index) | Up to 1 year | 
| Analysis of urine | Relative frequency of metabolites is measured in urine | Up to 1 year | 
| Biobanks samples | Secondary use of the biological samples in particular for research purposes | Up to 1 year | 
| Hip Osteoarthritis Outcome | Hip Osteoarthritis Outcome is measured from Hip disability and Osteoarthritis Outcome Score (HOOS) in orthopedic patients from PG cohort | Up to 1 year | 
| Knee Osteoarthritis Outcome | Knee Osteoarthritis Outcome is measured from Knee injury and Osteoarthritis Outcome (KOOS) in orthopedic patients from PG cohort | Up to 1 year | 
| Gait analysis 1 | Temporal (e.g.: total activity duration, stance time) parameters are measured in orthopedic patients from PG cohort. | Up to 1 year | 
| Gait analysis 2 | Kinetic parameters (e.g.: vertical plantar loading, loading symmetry) are measured in orthopedic patients from PG cohort. | Up to 1 year | 
| Range of Motion of the hip/knee | Range of Motion of the hip/knee is measured during orthopedic investigation of PG cohort patients | Up to 1 year | 
| Hip abduction force (for total hip arthroplasty patients) | Hip abduction force is measured during orthopedic investigation of PG cohort patients | Up to 1 year | 
| Knee extension and flexion force measurement (for total knee arthroplasty patients) | Knee extension and flexion force measurement is measured during orthopedic investigation of PG cohort patients | Up to 1 year | 
| Clinical investigation | Clinical investigation is measured by a neurosurgical method in patients from PG and NFC cohorts who undergo elective spine surgery and in control patients from NO cohort | Up to 1 year | 
| Oswestry disability index (ODI) | ODI is measured in patients from PG and NFC cohorts who undergo elective spine surgery and in control patients from NO cohort. | Up to 1 year | 
| Back pain | Low Back pain is measured by the Roland Morris Low Back pain and disability questionnaire in patients (PG, NFC, NO cohorts) with lumbal spine problems. | Up to 1 year | 
| Leg pain | Leg pain is measured by 100mm visual analog scale in patients (PG, NFC, NO cohorts) with lumbal spine problems. | Up to 1 year | 
| Sciatica Bothersomeness Index | To establish values for paresthesia, weakness and leg pain the Sciatica Bothersomeness Index is measured n patients (PG, NFC, NO cohorts) with lumbal spine problems. | Up to 1 year | 
| Disabilities of the Arm, Shoulder and Hand Questionnaire (DASH) | To measure Disabilities of the Arm, Shoulder and Hand the DASH questionnaire is used in patient (PG, NFC, NO cohort) in patients with cervical spine problems | Up to 1 year | 
| Modified Japanese orthopaedic association scale | The modified Japanese Orthopaedic Association scale is used to establish criteria for mild, moderate and severe impairment in patients with degenerative cervical myelopathy in patients (PG, NFC, NO cohorts) with cervical spine problems | Up to 1 year | 
| ASIA Impairment Scale (AIS) | ASIA Impairment Scale is used to measure for patients with spinal myelopathies or spinal cord injuries in patients from PG and NFC cohorts who undergo elective spine surgery and in control patients from NO cohort | Up to 1 year | 
| Skill management | Multiprofessional skill management is evaluated in all participating occupations of the GB cohort in qualitative interviews. | Up to 1 year | 
| Acceptance of participatory decision-making | Acceptance of participatory decision-making before and after participating in an SDM conference. | Up to 1 year | 
| Depth of anesthesia | Depth of anesthesia is measured by brainwaves in different patient states which range from awake, sedated, unresponsive, surgically anesthetized to deeply anesthetized. | During surgery, an expected average of 2 hours | 
| Electroencephalography spectral analysis | Electroencephalography spectral analysis is measured by brainwaves preoperatively. | During the hospital stay, at the beginning of the investigation, an average of one hour. | 
| Electroencephalography band power | Electroencephalography band power is measured postoperatively by an electroencephalography monitor at postoperative day 3 in all patients and in patients with delirium until 48 hours without positive delirium screening | During the hospital stay, an expected average of 1 week | 
| Effect of analgesics | Pain is evaluated with the Dolosys Paintracker. The Paintracker is a handy monitoring device to determine the analgesia needed for patients based on the pain reflex technique. | During the hospital stay, an expected average of 1 week |