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

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ClinicalTrials.gov Identifier: NCT02339649
Recruitment Status : Recruiting
First Posted : January 15, 2015
Last Update Posted : August 1, 2017
Sponsor:
Collaborator:
University Hospital, Bonn
Information provided by (Responsible Party):
German Center for Neurodegenerative Diseases (DZNE)

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Severe Sepsis With Septic Shock Severe Sepsis Without Septic Shock Procedure: Blood Sample Behavioral: Neurocognitive Assessment Other: Resting State EEG Procedure: Lumbar Puncture Other: MRI Not Applicable

Detailed Description:

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)

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 308 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary Purpose: Other
Official Title: Long-term Cognitive and Cerebral Changes in Sepsis Survivors and Their Predictors
Study Start Date : September 2013
Estimated Primary Completion Date : October 2017
Estimated Study Completion Date : October 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Sepsis Shock

Arm Intervention/treatment
Sepsis/septic Shock

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
Blood Sample

Behavioral: Neurocognitive Assessment
Neurocognitive Assessment

Other: Resting State EEG
10-20 Minutes of Resting State EEG
Other Name: Resting-State EEG

Procedure: Lumbar Puncture
Lumbar Puncture

Other: MRI
60 Minutes MRI

Postoperative ICU Patients

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
Blood Sample

Behavioral: Neurocognitive Assessment
Neurocognitive Assessment

Other: Resting State EEG
10-20 Minutes of Resting State EEG
Other Name: Resting-State EEG

Procedure: Lumbar Puncture
Lumbar Puncture

Other: MRI
60 Minutes MRI

Healthy Controls

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
Blood Sample

Behavioral: Neurocognitive Assessment
Neurocognitive Assessment

Other: Resting State EEG
10-20 Minutes of Resting State EEG
Other Name: Resting-State EEG

Procedure: Lumbar Puncture
Lumbar Puncture

Other: MRI
60 Minutes MRI




Primary Outcome Measures :
  1. Verbal Learning Memory Test Long Delayed Recall (Trial 7) [ Time Frame: 6 months post ICU ]
    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)


Secondary Outcome Measures :
  1. Verbal Learning Memory Test, German Version [ Time Frame: For patient groups: 6 months; for Healthy Controls: Baseline ]
    Verbal Learning and Memory: Verbal Learning Memory Test, German Version

  2. Verbal Learning Memory Test, German Version [ Time Frame: For patient groups: 12 months; for Healthy Controls: 6 months ]
    Verbal Learning and Memory: Verbal Learning Memory Test, German Version

  3. Wechsler Memory Scale IV Visual Recall I and II [ Time Frame: For patient groups: 6 months; for Healthy Controls: Baseline ]
    Visual Memory: Wechsler Memory Scale IV Visual Recall I and II

  4. Wechsler Memory Scale IV Visual Recall I and II [ Time Frame: For patient groups: 12 months; for Healthy Controls: 6 months ]
    Visual Memory: Wechsler Memory Scale IV Visual Recall I and II

  5. Wechsler Memory Scale Digit-Span [ Time Frame: For patient groups: 6 months; for Healthy Controls: Baseline ]
    Working Memory: Wechsler Memory Scale Digit-Span

  6. Wechsler Memory Scale Digit-Span [ Time Frame: For patient groups: 12 months; for Healthy Controls: 6 months ]
    Working Memory: Wechsler Memory Scale Digit-Span

  7. German Vocabulary Test [ Time Frame: For patient groups: 6 months; for Healthy Controls: Baseline ]
    Premorbid Verbal Ability: German Vocabulary Test Mehrfachwahl Wortschatztest B (MWT-B)

  8. German Vocabulary Test [ Time Frame: For patient groups: 12 months; for Healthy Controls: 6 months ]
    Premorbid Verbal Ability: German Vocabulary Test

  9. Symbol Digit Modalities Test [ Time Frame: For patient groups: 6 months; for Healthy Controls: Baseline ]
    Cognitive Speed

  10. Symbol Digit Modalities Test [ Time Frame: For patient groups: 12 months; for Healthy Controls: 6 months ]
    Cognitive Speed

  11. Trail Making Test A & B [ Time Frame: For patient groups: 6 months; for Healthy Controls: Baseline ]
    Simple and Divided Attention

  12. Trail Making Test A & B [ Time Frame: For patient groups: 12 months; for Healthy Controls: 6 months ]
    Simple and Divided Attention

  13. Phonetic and Lexical Verbal Fluency [ Time Frame: For patient groups: 6 months; for Healthy Controls: Baseline ]
    Phonetic and Lexical Verbal Fluency

  14. Phonetic and Lexical Verbal Fluency [ Time Frame: For patient groups: 12 months; for Healthy Controls: 6 months ]
    Phonetic and Lexical Verbal Fluency

  15. Patient Health Questionnaire Subtests Depression, Anxiety and Somatic Symptoms [ Time Frame: For patient groups: 6 months; for Healthy Controls: Baseline ]
    Depression and Anxiety Inventory

  16. Patient Health Questionnaire Subtests Depression, Anxiety and Somatic Symptoms [ Time Frame: For patient groups: 12 months; for Healthy Controls: 6 months ]
    Depression and Anxiety Inventory

  17. Post-Traumatic Stress Syndrome 10 [ Time Frame: For patient groups: 6 months; for Healthy Controls: Baseline ]
    Post-Traumatic Stress Screening

  18. Post-Traumatic Stress Syndrome 10 [ Time Frame: For patient groups: 12 months; for Healthy Controls: 6 months ]
    Post-Traumatic Stress Screening

  19. European Quality of Life 5 Dimensions-5 Levels [ Time Frame: For patient groups: 6 months; for Healthy Controls: Baseline ]
    Quality of Life

  20. European Quality of Life 5 Dimensions-5 Levels [ Time Frame: For patient groups: 12 months; for Healthy Controls: 6 months ]
    Quality of Life

  21. Functional Activities Questionnaire [ Time Frame: For patient groups: 6 months; for Healthy Controls: Baseline ]
    Activities of Daily Living

  22. Functional Activities Questionnaire [ Time Frame: For patient groups: 12 months; for Healthy Controls: 6 months ]
    Activities of Daily Living

  23. modified version of Rankin Scale Structured Interview (modified for ICU patients) [ Time Frame: For patient groups: 6 months; for Healthy Controls: Baseline ]
    Function Scale

  24. modified version of Rankin Scale Structured Interview (modified for ICU patients) [ Time Frame: For patient groups: 12 months; for Healthy Controls: 6 months ]
    Function Scale

  25. Pittsburgh Sleep Quality Index [ Time Frame: For patient groups: 6 months; for Healthy Controls: Baseline ]
    Sleep Quality

  26. Pittsburgh Sleep Quality Index [ Time Frame: For patient groups: 12 months; for Healthy Controls: 6 months ]
    Sleep Quality

  27. Mini Mental Status Examination [ Time Frame: For patient groups: (OP Probands 1-28 d before OP, 6 months; for Healthy Controls: Baseline ]
    Cognitive Screening

  28. Mini Mental Status Examination [ Time Frame: For patient groups: 12 months; for Healthy Controls: 6 months ]
    Cognitive Screening

  29. Clinical Scales at ICU [ Time Frame: For Patients during ICU Stay (Day 0, [Day 7 if still on ICU], Day of Release) ]
    Therapeutic Intervention Scoring System-10, Total Score Simplified Acute Physiology Score, Sequential Organ Failure Assessment Confusion Assessment Method for the ICU

  30. Neurological Examination [ Time Frame: For patient groups: 6 months, 12 months; for Healthy Controls: Baseline and 6 months ]
    Subscales Motor ability, Walking and Standing, Behavior, Praxis/Visual or Visuospatial, Speaking and Language, Autonomic Nervous System, Tone and Muscle Exam, Coordination and Movement

  31. resting state electroencephalogram [ Time Frame: For patient groups: 6 months, 12 months; for Healthy Controls: Baseline and 6 months ]
    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.

  32. MRI (3 Tesla) of brain with hippocampus as Region of Interest [ Time Frame: 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. 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

  33. Blood Sample [ Time Frame: For Patient Groups 2-3 samples during ICU, 3-4 Months, 6 months, 12 Months ]
    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.

  34. Lumbar Puncture (voluntary) [ Time Frame: 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 ]
    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



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   25 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02339649


Contacts
Contact: Catherine N. Widmann, M.A. +49 (0)228 287 13093 catherine.widmann@dzne.de
Contact: Michael T. Heneka, MD +49 (0)228 287 13091 michael.heneka@dzne.de

Locations
Germany
Department of Anesthesiology, University Hospital Bonn Recruiting
Bonn, North Rhine-Westphalia (NRW), Germany, 53105
DZNE Center for Clinical Research Not yet recruiting
Bonn, Northrhine-Westphalia, Germany, 53117
Sponsors and Collaborators
German Center for Neurodegenerative Diseases (DZNE)
University Hospital, Bonn
Investigators
Principal Investigator: Michael T Heneka, M.D. German Center for Neurodegenerative Diseases (DZNE)
Study Chair: Andreas Hoeft, M.D. Department of Anesthesiology and Intensive Care Medicine, University Hospital Bonn
Study Chair: Christian Putensen, M.D. Research Unit Pulmonary Dysfunction and Sepsis, Department of Anesthesiology and Intensive Care Medicine, University Hospital Bonn
Study Chair: Thomas Klockgether, M.D. German Center for Neurodegenerative Diseases (DZNE)

Additional Information:
Publications:

Responsible Party: German Center for Neurodegenerative Diseases (DZNE)
ClinicalTrials.gov Identifier: NCT02339649     History of Changes
Other Study ID Numbers: BN005
2011-003014-16 ( EudraCT Number )
First Posted: January 15, 2015    Key Record Dates
Last Update Posted: August 1, 2017
Last Verified: July 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Keywords provided by German Center for Neurodegenerative Diseases (DZNE):
sepsis
septic shock
ICU
long-term outcome
neurocognitive
inflammatory
MRI
EEG
brain imaging
serum biomarkers
CSF

Additional relevant MeSH terms:
Sepsis
Toxemia
Shock
Shock, Septic
Infection
Systemic Inflammatory Response Syndrome
Inflammation
Pathologic Processes