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Severe Sepsis With Septic ShockBonSEPNCT02339649

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

A study testing Blood Sample, Neurocognitive Assessment and Resting State EEG in people with Severe Sepsis With Septic Shock and Severe Sepsis Without Septic Shock, run by German Center for Neurodegenerative Diseases (DZNE) at 2 sites in Germany.

Unknown status

Status not confirmed. The sponsor has not verified this record for over two years, so it may be out of date.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 25 to 80 yearsHealthy volunteers can take part
What is being tested?
Blood Sample, Neurocognitive Assessment and Resting State EEG
Could I receive a placebo?
No, everyone receives an active treatment
How many people
308 participants
Where
2 sitesGermany
Study dates
Sep 2013to Oct 2019
Phase
Interventional
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 25 to 80 years
  • All sexes
  • Healthy volunteers accepted
  • Adult, Older adult

Who may be able to join

  • 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.
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  • 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

Who cannot join

  • 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
Show all 19Show fewer
  • 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

Trial locations and contacts

2 sites in 1 country.

Catherine N. Widmann, M.A. contact

+49 (0)228 287 13093

catherine.widmann@dzne.de

Michael T. Heneka, MD contact

+49 (0)228 287 13091

michael.heneka@dzne.de

Germany2 sites, 2 recruiting

  • DZNE Center for Clinical Research

    Bonn, North Rhine-Westphalia, 53117

    Not yet recruiting

  • Department of Anesthesiology, University Hospital Bonn

    Bonn, North Rhine-Westphalia (nrw), 53105

    Recruiting

Other trials in Germany

About this study

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.

Read the 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)
Being tested
Blood Sample, Neurocognitive Assessment, Resting State EEG, Lumbar Puncture, MRI
Keywords
sepsis, septic shock, ICU, long-term outcome, neurocognitive, inflammatory, MRI, EEG, brain imaging, serum biomarkers, CSF
Medical subject headings
Sepsis, Shock, Septic

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Blood SampleProcedure or surgery

    Blood Sample

  • Neurocognitive AssessmentBehavioural

    Neurocognitive Assessment

  • Resting State EEGOther

    Also called Resting-State EEG

    10-20 Minutes of Resting State EEG

  • Lumbar PunctureProcedure or surgery

    Lumbar Puncture

  • MRIOther

    60 Minutes MRI

Study groups in NCT02339649
Study groupRoleWhat they receive
Sepsis/septic ShockOtherMen 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
Receives: Procedure: Blood Sample; Behavioral: Neurocognitive Assessment; Other: Resting State EEG; Procedure: Lumbar Puncture; Other: MRI
Postoperative ICU PatientsOtherMen 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
Receives: Procedure: Blood Sample; Behavioral: Neurocognitive Assessment; Other: Resting State EEG; Procedure: Lumbar Puncture; Other: MRI
Healthy ControlsOtherHealthy 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
Receives: Procedure: Blood Sample; Behavioral: Neurocognitive Assessment; Other: Resting State EEG; Procedure: Lumbar Puncture; Other: MRI

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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)

    Measured: 6 months post ICU

Secondary outcomes (34)

  1. Verbal Learning Memory Test, German Version

    Verbal Learning and Memory: Verbal Learning Memory Test, German Version

    Measured: For patient groups: 6 months; for Healthy Controls: Baseline

  2. Verbal Learning Memory Test, German Version

    Verbal Learning and Memory: Verbal Learning Memory Test, German Version

    Measured: For patient groups: 12 months; for Healthy Controls: 6 months

  3. Wechsler Memory Scale IV Visual Recall I and II

    Visual Memory: Wechsler Memory Scale IV Visual Recall I and II

    Measured: For patient groups: 6 months; for Healthy Controls: Baseline

  4. Wechsler Memory Scale IV Visual Recall I and II

    Visual Memory: Wechsler Memory Scale IV Visual Recall I and II

    Measured: For patient groups: 12 months; for Healthy Controls: 6 months

  5. Wechsler Memory Scale Digit-Span

    Working Memory: Wechsler Memory Scale Digit-Span

    Measured: For patient groups: 6 months; for Healthy Controls: Baseline

  6. Wechsler Memory Scale Digit-Span

    Working Memory: Wechsler Memory Scale Digit-Span

    Measured: For patient groups: 12 months; for Healthy Controls: 6 months

  7. German Vocabulary Test

    Premorbid Verbal Ability: German Vocabulary Test Mehrfachwahl Wortschatztest B (MWT-B)

    Measured: For patient groups: 6 months; for Healthy Controls: Baseline

  8. German Vocabulary Test

    Premorbid Verbal Ability: German Vocabulary Test

    Measured: For patient groups: 12 months; for Healthy Controls: 6 months

  9. Symbol Digit Modalities Test

    Cognitive Speed

    Measured: For patient groups: 6 months; for Healthy Controls: Baseline

  10. Symbol Digit Modalities Test

    Cognitive Speed

    Measured: For patient groups: 12 months; for Healthy Controls: 6 months

  11. Trail Making Test A & B

    Simple and Divided Attention

    Measured: For patient groups: 6 months; for Healthy Controls: Baseline

  12. Trail Making Test A & B

    Simple and Divided Attention

    Measured: For patient groups: 12 months; for Healthy Controls: 6 months

  13. Phonetic and Lexical Verbal Fluency

    Phonetic and Lexical Verbal Fluency

    Measured: For patient groups: 6 months; for Healthy Controls: Baseline

  14. Phonetic and Lexical Verbal Fluency

    Phonetic and Lexical Verbal Fluency

    Measured: For patient groups: 12 months; for Healthy Controls: 6 months

  15. Patient Health Questionnaire Subtests Depression, Anxiety and Somatic Symptoms

    Depression and Anxiety Inventory

    Measured: For patient groups: 6 months; for Healthy Controls: Baseline

  16. Patient Health Questionnaire Subtests Depression, Anxiety and Somatic Symptoms

    Depression and Anxiety Inventory

    Measured: For patient groups: 12 months; for Healthy Controls: 6 months

  17. Post-Traumatic Stress Syndrome 10

    Post-Traumatic Stress Screening

    Measured: For patient groups: 6 months; for Healthy Controls: Baseline

  18. Post-Traumatic Stress Syndrome 10

    Post-Traumatic Stress Screening

    Measured: For patient groups: 12 months; for Healthy Controls: 6 months

  19. European Quality of Life 5 Dimensions-5 Levels

    Quality of Life

    Measured: For patient groups: 6 months; for Healthy Controls: Baseline

  20. European Quality of Life 5 Dimensions-5 Levels

    Quality of Life

    Measured: For patient groups: 12 months; for Healthy Controls: 6 months

  21. Functional Activities Questionnaire

    Activities of Daily Living

    Measured: For patient groups: 6 months; for Healthy Controls: Baseline

  22. Functional Activities Questionnaire

    Activities of Daily Living

    Measured: For patient groups: 12 months; for Healthy Controls: 6 months

  23. modified version of Rankin Scale Structured Interview (modified for ICU patients)

    Function Scale

    Measured: For patient groups: 6 months; for Healthy Controls: Baseline

  24. modified version of Rankin Scale Structured Interview (modified for ICU patients)

    Function Scale

    Measured: For patient groups: 12 months; for Healthy Controls: 6 months

  25. Pittsburgh Sleep Quality Index

    Sleep Quality

    Measured: For patient groups: 6 months; for Healthy Controls: Baseline

  26. Pittsburgh Sleep Quality Index

    Sleep Quality

    Measured: For patient groups: 12 months; for Healthy Controls: 6 months

  27. Mini Mental Status Examination

    Cognitive Screening

    Measured: For patient groups: (OP Probands 1-28 d before OP, 6 months; for Healthy Controls: Baseline

  28. Mini Mental Status Examination

    Cognitive Screening

    Measured: For patient groups: 12 months; for Healthy Controls: 6 months

  29. 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

    Measured: For Patients during ICU Stay (Day 0, [Day 7 if still on ICU], Day of Release)

  30. 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

    Measured: For patient groups: 6 months, 12 months; for Healthy Controls: Baseline and 6 months

  31. 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.

    Measured: For patient groups: 6 months, 12 months; for Healthy Controls: Baseline and 6 months

  32. 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

    Measured: For patient groups: 6 months, 12 months; for Healthy Controls: Baseline and 6 months

  33. 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.

    Measured: For Patient Groups 2-3 samples during ICU, 3-4 Months, 6 months, 12 Months

  34. 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

    Measured: 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

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted15 Jan 2015 (estimated)
  2. Study startSep 2013
  3. Primary completionOct 2017 (estimated)
  4. Study completionOct 2019 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase N/A
Primary purpose
Other
Allocation
Non-randomised
Intervention model
Parallel groups
Masking
Single blind
Who is masked
Outcomes assessor
Enrolment
308 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02339649
Sponsor's protocol ID
BN005
Other IDs
2011-003014-16
Acronym
BonSEP
Status last verified
Jul 2017
First submitted
3 Aug 2011
Last updated
1 Aug 2017
Results posted
No
Data monitoring committee
Yes
Individual data sharing
No

Publications

  • Weberpals M, Hermes M, Hermann S, Kummer MP, Terwel D, Semmler A, Berger M, Schafers M, Heneka MT. NOS2 gene deficiency protects from sepsis-induced long-term cognitive deficits. J Neurosci. 2009 Nov 11;29(45):14177-84. doi: 10.1523/JNEUROSCI.3238-09.2009.

    PubMed 19906966

  • Pandharipande PP, Girard TD, Jackson JC, Morandi A, Thompson JL, Pun BT, Brummel NE, Hughes CG, Vasilevskis EE, Shintani AK, Moons KG, Geevarghese SK, Canonico A, Hopkins RO, Bernard GR, Dittus RS, Ely EW; BRAIN-ICU Study Investigators. Long-term cognitive impairment after critical illness. N Engl J Med. 2013 Oct 3;369(14):1306-16. doi: 10.1056/NEJMoa1301372.

    PubMed 24088092

  • Semmler A, Widmann CN, Okulla T, Urbach H, Kaiser M, Widman G, Mormann F, Weide J, Fliessbach K, Hoeft A, Jessen F, Putensen C, Heneka MT. Persistent cognitive impairment, hippocampal atrophy and EEG changes in sepsis survivors. J Neurol Neurosurg Psychiatry. 2013 Jan;84(1):62-9. doi: 10.1136/jnnp-2012-302883. Epub 2012 Nov 7.

    PubMed 23134661

  • Sonneville R, Verdonk F, Rauturier C, Klein IF, Wolff M, Annane D, Chretien F, Sharshar T. Understanding brain dysfunction in sepsis. Ann Intensive Care. 2013 May 29;3(1):15. doi: 10.1186/2110-5820-3-15.

    PubMed 23718252

  • Iwashyna TJ, Ely EW, Smith DM, Langa KM. Long-term cognitive impairment and functional disability among survivors of severe sepsis. JAMA. 2010 Oct 27;304(16):1787-94. doi: 10.1001/jama.2010.1553.

    PubMed 20978258

  • Widmann CN, Heneka MT. Long-term cerebral consequences of sepsis. Lancet Neurol. 2014 Jun;13(6):630-6. doi: 10.1016/S1474-4422(14)70017-1.

    PubMed 24849863

  • Widmann CN, Schewe JC, Heneka MT. Sepsis-associated encephalopathy versus sepsis-induced encephalopathy--authors' reply. Lancet Neurol. 2014 Oct;13(10):968-9. doi: 10.1016/S1474-4422(14)70204-2. No abstract available.

    PubMed 25231518

  • Lindlau A, Widmann CN, Putensen C, Jessen F, Semmler A, Heneka MT. Predictors of hippocampal atrophy in critically ill patients. Eur J Neurol. 2015 Feb;22(2):410-5. doi: 10.1111/ene.12443. Epub 2014 Apr 12.

    PubMed 24724819

Questions about this trial

What is this clinical trial studying?

A study testing Blood Sample, Neurocognitive Assessment and Resting State EEG in people with Severe Sepsis With Septic Shock and Severe Sepsis Without Septic Shock, run by German Center for Neurodegenerative Diseases (DZNE) at 2 sites in Germany.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 18 inclusion and 19 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: status not confirmed, as of the sponsor's last update on 1 Aug 2017. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites in Germany. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

Are results available for this study?

Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

Contact Catherine N. Widmann, M.A. (+49 (0)228 287 13093, catherine.widmann@dzne.de), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Verbal Learning Memory Test Long Delayed Recall (Trial 7) (time frame: 6 months post ICU). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02339649, which also lists 8 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 Aug 2017.

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