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

Severe Sepsis With Septic Shock Clinical Trial

— BonSEP  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02339649
• Other study ID #: BN005
• Secondary ID: 2011-003014-16
• Status: Recruiting
• Phase: N/A
• First received: August 3, 2011
• Last updated: July 28, 2017
• Start date: September 2013
• Est. completion date: October 2019

Study information

• Verified date: July 2017
• Source: German Center for Neurodegenerative Diseases (DZNE)
• Contact: Catherine N. Widmann, M.A.
• Phone: +49 (0)228 287 13093
• Email: catherine.widmann[@]dzne.de
• Is FDA regulated: No
• Study type: Interventional

Clinical 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.

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)

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 308
• Est. completion date: October 2019
• Est. primary completion date: October 2017
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 25 Years to 80 Years

Eligibility

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

Related Conditions & MeSH terms

• Sepsis
• Severe Sepsis With Septic Shock
• Severe Sepsis Without Septic Shock
• Shock
• Shock, Septic
• Toxemia

Intervention

Procedure:
• Blood Sample
Blood Sample

Behavioral:
• Neurocognitive Assessment
Neurocognitive Assessment

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

Procedure:
• Lumbar Puncture
Lumbar Puncture

Other:
• MRI
60 Minutes MRI

Locations

Country	Name	City	State
Germany	Department of Anesthesiology, University Hospital Bonn	Bonn	North Rhine-Westphalia (NRW)
Germany	DZNE Center for Clinical Research	Bonn	Northrhine-Westphalia

Sponsors (2)

Lead Sponsor	Collaborator
German Center for Neurodegenerative Diseases (DZNE)	University Hospital, Bonn

Country where clinical trial is conducted

Germany, 

References & Publications (8)

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Weberpals M, Hermes M, Hermann S, Kummer MP, Terwel D, Semmler A, Berger M, Schäfers 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. — View Citation

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Wechsler Memory Scale Digit-Span	Working Memory: Wechsler Memory Scale Digit-Span	For patient groups: 6 months; for Healthy Controls: Baseline
Secondary	Wechsler Memory Scale Digit-Span	Working Memory: Wechsler Memory Scale Digit-Span	For patient groups: 12 months; for Healthy Controls: 6 months
Secondary	German Vocabulary Test	Premorbid Verbal Ability: German Vocabulary Test Mehrfachwahl Wortschatztest B (MWT-B)	For patient groups: 6 months; for Healthy Controls: Baseline
Secondary	German Vocabulary Test	Premorbid Verbal Ability: German Vocabulary Test	For patient groups: 12 months; for Healthy Controls: 6 months
Secondary	Symbol Digit Modalities Test	Cognitive Speed	For patient groups: 6 months; for Healthy Controls: Baseline
Secondary	Symbol Digit Modalities Test	Cognitive Speed	For patient groups: 12 months; for Healthy Controls: 6 months
Secondary	Trail Making Test A & B	Simple and Divided Attention	For patient groups: 6 months; for Healthy Controls: Baseline
Secondary	Trail Making Test A & B	Simple and Divided Attention	For patient groups: 12 months; for Healthy Controls: 6 months
Secondary	Phonetic and Lexical Verbal Fluency	Phonetic and Lexical Verbal Fluency	For patient groups: 6 months; for Healthy Controls: Baseline
Secondary	Phonetic and Lexical Verbal Fluency	Phonetic and Lexical Verbal Fluency	For patient groups: 12 months; for Healthy Controls: 6 months
Secondary	Patient Health Questionnaire Subtests Depression, Anxiety and Somatic Symptoms	Depression and Anxiety Inventory	For patient groups: 6 months; for Healthy Controls: Baseline
Secondary	Patient Health Questionnaire Subtests Depression, Anxiety and Somatic Symptoms	Depression and Anxiety Inventory	For patient groups: 12 months; for Healthy Controls: 6 months
Secondary	Post-Traumatic Stress Syndrome 10	Post-Traumatic Stress Screening	For patient groups: 6 months; for Healthy Controls: Baseline
Secondary	Post-Traumatic Stress Syndrome 10	Post-Traumatic Stress Screening	For patient groups: 12 months; for Healthy Controls: 6 months
Secondary	European Quality of Life 5 Dimensions-5 Levels	Quality of Life	For patient groups: 6 months; for Healthy Controls: Baseline
Secondary	European Quality of Life 5 Dimensions-5 Levels	Quality of Life	For patient groups: 12 months; for Healthy Controls: 6 months
Secondary	Functional Activities Questionnaire	Activities of Daily Living	For patient groups: 6 months; for Healthy Controls: Baseline
Secondary	Functional Activities Questionnaire	Activities of Daily Living	For patient groups: 12 months; for Healthy Controls: 6 months
Secondary	modified version of Rankin Scale Structured Interview (modified for ICU patients)	Function Scale	For patient groups: 6 months; for Healthy Controls: Baseline
Secondary	modified version of Rankin Scale Structured Interview (modified for ICU patients)	Function Scale	For patient groups: 12 months; for Healthy Controls: 6 months
Secondary	Pittsburgh Sleep Quality Index	Sleep Quality	For patient groups: 6 months; for Healthy Controls: Baseline
Secondary	Pittsburgh Sleep Quality Index	Sleep Quality	For patient groups: 12 months; for Healthy Controls: 6 months
Secondary	Mini Mental Status Examination	Cognitive Screening	For patient groups: (OP Probands 1-28 d before OP, 6 months; for Healthy Controls: Baseline
Secondary	Mini Mental Status Examination	Cognitive Screening	For patient groups: 12 months; for Healthy Controls: 6 months
Secondary	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)
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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 t, phospho-t, ß-amyloid 1 40 and ß-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

External Links

•   Clinical Neuroscience Unit, Department of Neurology, University Hospital Bonn
•   Department of Anesthesiology, University Hospital Bonn
•   German Center for Neurodegenerative Disease (DZNE)