Long-term Cognitive and Cerebral Changes in Sepsis Survivors and Their Predictors

Study Overview
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Brief Summary
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The main goals of this study are to provide a cognitive, neurological, brain morphological, and serological profile of sepsis survivors in order to make long-term prognosis of recovery and estimate the need for rehabilitation measures in order to help patients reintegrate into normal daily life.

Detailed Description
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Comparison of cognitive function in severe septic/septic shock ICU patients with non-septic postoperative ICU patients and actively recruited healthy controls at several time points up to 12 months after leaving the ICU. Secondary aims: Profiling specific cognitive deficits in sepsis survivors over time. Identifying possible subclasses of long-term cognitive impairment according to facets of disease, therapy and ICU experience. Investigating long-term brain morphological changes, with hippocampus as region of interest (ROI). Determining values of Serum- and CSF-Biomarkers Evaluation of diagnostic and prognostic value of non-routine biomarkers for systemic- and neuroinflammation in the acute phase and in the long-term Investigate associations between brain morphological changes, cognitive changes, neurological status, psychiatric burden, disability level, employment status and health-related quality of life (HRQOL). Investigating brain-activity changes in resting state electro-encephalogram (EEG)

Official Title
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Long-term Cognitive and Cerebral Changes in Sepsis Survivors and Their Predictors

Conditions
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Severe Sepsis With Septic Shock, Severe Sepsis Without Septic Shock

Intervention / Treatment
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* Procedure: Blood Sample
* Behavioral: Neurocognitive Assessment
* Other: Resting State EEG
* Procedure: Lumbar Puncture
* Other: MRI


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: sepsis/septic shock subjects will only be included in the study if they meet all of the following criteria: Written informed consent of the subject. or legal representative patient at the Anesthesiological-Operative Intensive Care Unit of the University Hospital Bonn, the Department of Anesthesiology, Intensive Care and Pain Therapy of the Malteser Hospital, or the Department of Anesthesiology, Intensive Care Medicine and Pain Medicine of the Gemeinschaftskrankenhaus Bonn St. Petrus Hospital. At the Anesthesiological-Operative Intensive Care Unit of the University Hospital Bonn, only, or 1) documentation of presumed will via a relative or legal representative . together with 2) Documentation of verification by a doctor independent of the study that the patient's study participation is unobjectionable. Written informed consent of patient will be obtained at the earliest time possible. Aged 25-80 years Male or female Admitted to the intensive care units of the Anesthesiological-Operative Intensive Care Unit of the University Hospital Bonn, from the Department of Anesthesiology, Intensive Care and Pain Therapy of the Malteser Hospital or from the Department of Anesthesiology, Intensive Care Medicine and Pain Medicine of the Gemeinschaftskrankenhaus Bonn St. Petrus Hospital. Duration of ICU stay must be a minimum of 24 hours. In case of transfer to intermediate care or the observation ward before the 24 hour ICU period is complete, study parameters must be allowed to be assessed. Fulfill the criteria of sepsis and/or septic shock patients according to theThird International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3, Singer et al, 2016). Postoperative ICU Patients will only be included in the study if they meet all of the following criteria: Written informed consent of the subject. Aged 25-80 years Male or female Admitted to the intensive care units of the Anesthesiological-Operative Intensive Care Unit of the University Hospital Bonn, which includes a surgical ICU, an anesthesiological ICU, and a cardio-surgical ICU Duration of ICU stay must be a minimum of 24 hours. In case of transfer to intermediate care or the observation ward before the 24 hour ICU period is complete, study parameters must be allowed to be assessed. Mini-Mental Status Examination (MMSE) Score of 25 or above Healthy Controls will only be included in the study if they meet all of the following criteria: Written informed consent of the subject Aged 25-80 years Male or female EXCLUSION CRITERIA: Subjects presenting with any of the following exclusion criteria may not be included in the study: Simultaneous participation in any clinical treatment study involving administration of an investigational medicinal product within 30 days prior to study beginning Physical or psychiatric condition which at the investigator's discretion may put the subject at risk, may confound the study results, or may interfere with the subject's participation in this study Prior to the start of this study existence of preexisting severe diseases and/or conduction of surgery necessarily imply life expectancy less than 12 months Known or suspected persistent abuse of medication, drugs or alcohol now or in the past Known cerebral lesions, cerebral infarction or malignomas Dementia or history of other central nervous system diseases Cranial-cerebral injury Known HIV-Infection Known liver cirrhosis with a documented Child-Pugh Score of C prior to this study Liver transplants Prior to start of this study nursing care level of 2 or 3 Prior to start of this study residing in a nursing home Additional Exclusion Criteria For Non-Septic Postoperative ICU Patients: Fulfill the criteria of sepsis and/or septic shock patients according to theThird International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3, Singer et al, 2016). In the case that a postoperative ICU patient fulfills the criteria for sepsis during ICU stay, he/she will be moved to the sepsis group. Additional Exclusion Criteria For Healthy: Executing third-party cognitive and functional assessments of another patient-subject also included in this investigation History of ICU stay in the last 12 months

Ages Eligible for Study
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Minimum Age: 25 Years
Maximum Age: 80 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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Design Details

Primary Purpose: Other
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Sepsis/septic Shock<br>Men and women seen at the intensive care units of the Anesthesiology Department of the University Hospital Bonn aged 25-80; fulfill the criteria of sepsis and/or septic shock patients according to theThird International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3, Singer et al, 2016). Interventions: Neurocognitive Assessment, Clinical Scales, Questionnaires, Blood Sample, voluntary Lumbar Puncture, Resting State EEG, MRI | Procedure: Blood Sample<br>* Blood Sample<br>Behavioral: Neurocognitive Assessment<br>* Neurocognitive Assessment<br>Other: Resting State EEG<br>* 10-20 Minutes of Resting State EEG<br>* Other names: Resting-State EEG;Procedure: Lumbar Puncture<br>* Lumbar Puncture<br>Other: MRI<br>* 60 Minutes MRI<br>|
| Other: Postoperative ICU Patients<br>Men and women seen at the intensive care units of the Anesthesiology Department of the University Hospital Bonn aged 25-80: Admitted to the intensive care units of the Anesthesiological-Operative Intensive Care Unit of the University Hospital Bonn, which includes a surgical ICU, an anesthesiological ICU, and a cardio-surgical ICU Duration of ICU stay must be a minimum of 24 hours. Mini-Mental State Examination (MMSE) Score of 25 or above Interventions: Neurocognitive Assessment, Clinical Scales, Questionnaires, Blood Sample, voluntary Lumbar Puncture, Resting State EEG, MRI | Procedure: Blood Sample<br>* Blood Sample<br>Behavioral: Neurocognitive Assessment<br>* Neurocognitive Assessment<br>Other: Resting State EEG<br>* 10-20 Minutes of Resting State EEG<br>* Other names: Resting-State EEG;Procedure: Lumbar Puncture<br>* Lumbar Puncture<br>Other: MRI<br>* 60 Minutes MRI<br>|
| Other: Healthy Controls<br>Healthy Controls will only be included in the study if they meet all of the following criteria: Written informed consent of the subject, Aged 25-80 years, Male or female. Interventions: Neurocognitive Assessment, Clinical Scales, Questionnaires, Blood Sample, voluntary Lumbar Puncture, Resting State EEG, MRI | Procedure: Blood Sample<br>* Blood Sample<br>Behavioral: Neurocognitive Assessment<br>* Neurocognitive Assessment<br>Other: Resting State EEG<br>* 10-20 Minutes of Resting State EEG<br>* Other names: Resting-State EEG;Procedure: Lumbar Puncture<br>* Lumbar Puncture<br>Other: MRI<br>* 60 Minutes MRI<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Verbal Learning Memory Test Long Delayed Recall (Trial 7) | Verbal Learning Memory Test Long Delayed Recall (Trial 7) at 6 months post ICU admission in sepsis/septic shock patients versus non-septic postoperative patients, and comparison to actively recruited healthy controls) | 6 months post ICU | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Verbal Learning Memory Test, German Version | Verbal Learning and Memory: Verbal Learning Memory Test, German Version | For patient groups: 6 months; for Healthy Controls: Baseline | 
| Verbal Learning Memory Test, German Version | Verbal Learning and Memory: Verbal Learning Memory Test, German Version | For patient groups: 12 months; for Healthy Controls: 6 months | 
| Wechsler Memory Scale IV Visual Recall I and II | Visual Memory: Wechsler Memory Scale IV Visual Recall I and II | For patient groups: 6 months; for Healthy Controls: Baseline | 
| Wechsler Memory Scale IV Visual Recall I and II | Visual Memory: Wechsler Memory Scale IV Visual Recall I and II | For patient groups: 12 months; for Healthy Controls: 6 months | 
| Wechsler Memory Scale Digit-Span | Working Memory: Wechsler Memory Scale Digit-Span | For patient groups: 6 months; for Healthy Controls: Baseline | 
| Wechsler Memory Scale Digit-Span | Working Memory: Wechsler Memory Scale Digit-Span | For patient groups: 12 months; for Healthy Controls: 6 months | 
| German Vocabulary Test | Premorbid Verbal Ability: German Vocabulary Test Mehrfachwahl Wortschatztest B (MWT-B) | For patient groups: 6 months; for Healthy Controls: Baseline | 
| German Vocabulary Test | Premorbid Verbal Ability: German Vocabulary Test | For patient groups: 12 months; for Healthy Controls: 6 months | 
| Symbol Digit Modalities Test | Cognitive Speed | For patient groups: 6 months; for Healthy Controls: Baseline | 
| Symbol Digit Modalities Test | Cognitive Speed | For patient groups: 12 months; for Healthy Controls: 6 months | 
| Trail Making Test A & B | Simple and Divided Attention | For patient groups: 6 months; for Healthy Controls: Baseline | 
| Trail Making Test A & B | Simple and Divided Attention | For patient groups: 12 months; for Healthy Controls: 6 months | 
| Phonetic and Lexical Verbal Fluency | Phonetic and Lexical Verbal Fluency | For patient groups: 6 months; for Healthy Controls: Baseline | 
| Phonetic and Lexical Verbal Fluency | Phonetic and Lexical Verbal Fluency | For patient groups: 12 months; for Healthy Controls: 6 months | 
| Patient Health Questionnaire Subtests Depression, Anxiety and Somatic Symptoms | Depression and Anxiety Inventory | For patient groups: 6 months; for Healthy Controls: Baseline | 
| Patient Health Questionnaire Subtests Depression, Anxiety and Somatic Symptoms | Depression and Anxiety Inventory | For patient groups: 12 months; for Healthy Controls: 6 months | 
| Post-Traumatic Stress Syndrome 10 | Post-Traumatic Stress Screening | For patient groups: 6 months; for Healthy Controls: Baseline | 
| Post-Traumatic Stress Syndrome 10 | Post-Traumatic Stress Screening | For patient groups: 12 months; for Healthy Controls: 6 months | 
| European Quality of Life 5 Dimensions-5 Levels | Quality of Life | For patient groups: 6 months; for Healthy Controls: Baseline | 
| European Quality of Life 5 Dimensions-5 Levels | Quality of Life | For patient groups: 12 months; for Healthy Controls: 6 months | 
| Functional Activities Questionnaire | Activities of Daily Living | For patient groups: 6 months; for Healthy Controls: Baseline | 
| Functional Activities Questionnaire | Activities of Daily Living | For patient groups: 12 months; for Healthy Controls: 6 months | 
| modified version of Rankin Scale Structured Interview (modified for ICU patients) | Function Scale | For patient groups: 6 months; for Healthy Controls: Baseline | 
| modified version of Rankin Scale Structured Interview (modified for ICU patients) | Function Scale | For patient groups: 12 months; for Healthy Controls: 6 months | 
| Pittsburgh Sleep Quality Index | Sleep Quality | For patient groups: 6 months; for Healthy Controls: Baseline | 
| Pittsburgh Sleep Quality Index | Sleep Quality | For patient groups: 12 months; for Healthy Controls: 6 months | 
| Mini Mental Status Examination | Cognitive Screening | For patient groups: (OP Probands 1-28 d before OP, 6 months; for Healthy Controls: Baseline | 
| Mini Mental Status Examination | Cognitive Screening | For patient groups: 12 months; for Healthy Controls: 6 months | 
| Clinical Scales at ICU | Therapeutic Intervention Scoring System-10, Total Score Simplified Acute Physiology Score, Sequential Organ Failure Assessment Confusion Assessment Method for the ICU | For Patients during ICU Stay (Day 0, [Day 7 if still on ICU], Day of Release) | 
| Neurological Examination | Subscales Motor ability, Walking and Standing, Behavior, Praxis/Visual or Visuospatial, Speaking and Language, Autonomic Nervous System, Tone and Muscle Exam, Coordination and Movement | For patient groups: 6 months, 12 months; for Healthy Controls: Baseline and 6 months | 
| resting state electroencephalogram | 10-20 system electroencephalogram (64 channels with additional electro-oculogram, electromyogram, electrocardiogram). The protocol includes 5 phases, each one minute long: 1) eyes open, relaxed state, fixation of a black dot at 2 m distance, 2) word generation using letter P with eyes closed, 3) mental arithmetic: continuous subtraction of 7 starting from 1,000 with eyes closed, 4) eyes closed, relaxed state, no task, 5) visualization of a previously memorized geometric figure with eyes closed. Data sampled at a rate of 256 Herz using an anti-aliasing low pass filter. Power spectra will be calculated for consecutive 4-second windows and calculated for each electrode contact. Absolute spectral power will be determined for the delta (0.5-4 Herz), theta (4-8 Herz), alpha (8-13 Herz), beta (13-20 Herz) and gamma (20-40 Herz) bands, which will be averaged across all windows. | For patient groups: 6 months, 12 months; for Healthy Controls: Baseline and 6 months | 
| MRI (3 Tesla) of brain with hippocampus as Region of Interest | MRI (3 Tesla) of brain with hippocampus as Region of Interest. Protocol includes: three-dimensional, T1-weighted rapid gradient echo sequence, Resting State, Gradient Echo-Field-Map for Resting State, Inversion Recovery Echo Planar Imaging for Resting State, Spoiled Gradient Echo, Fluid Attenuated inversion Recovery, Susceptibility weighted imaging, Diffusion Tensor Imaging, Gradient Echo-Field-Map for Diffusion Tensor Imaging | For patient groups: 6 months, 12 months; for Healthy Controls: Baseline and 6 months | 
| Blood Sample | All blood samples shall be drawn, stored and analyzed according to the participant information in the laboratories of the Biomarker Dementia Working Group and the Central Laboratory. Blood sampling analysis will include leukocyte count, hemoglobin, hematocrit, erythrocytes, Mean Corpuscular Hemoglobin, Meam Corpuscular Volume, mean Corpuscular Hemoglobin Concentration, Thrombocytes, Glucose, Lactate, electrolytes Sodium, Potassium, Calcium, Cholesterine, Tumor necrosis Factor-alpha, Interleukin-1 alpha, Interleukin-1 beta, Interleukin-6, C-reactive protein, Neuron Specific Enolase, Procalcitonin, S-100 Protein, as well as DNA and serum biorepository for further scientific analysis. | For Patient Groups 2-3 samples during ICU, 3-4 Months, 6 months, 12 Months | 
| Lumbar Puncture (voluntary) | Cerebrospinal fluid (CSF) routine parameters will be analyzed by the Central Laboratory. Results will then be provided to the investigator. For determination of τ, phospho-τ, β-amyloid 1 40 and β-amyloid 1 42, 5 ml of cerebral-spinal-fluid will be analyzed at the laboratories of the German Center for Neurodegenerative Diseases (DZNE), Biomarker Dementia Working Group, Sigmund-Freud-Str. 25, 53105 Bonn | For Patients: (while at ICU, if clinically indicated as part of clinical routine and only if patient directly gives informed consent), 12 months; For Healthy Controls: Baseline and 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ICU, sepsis, septic shock, long-term outcome, neurocognitive, inflammatory, MRI, EEG, brain imaging, serum biomarkers, CSF