Clinical trial NCT02339649: Long-term Cognitive and Cerebral Changes in Sepsis Survivors and Their Predictors
Official title: Long-term Cognitive and Cerebral Changes in Sepsis Survivors and Their Predictors
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Severe Sepsis With Septic Shock
Severe Sepsis Without Septic Shock
Keywords: sepsis
septic shock
ICU
long-term outcome
neurocognitive
inflammatory
MRI
EEG
brain imaging
serum biomarkers
CSF
Lead sponsor: German Center for Neurodegenerative Diseases (DZNE)
Sponsor class: OTHER
Collaborators: name: University Hospital, Bonn
First posted: 2015-01-15
Enrollment: 308
Sex: ALL
Minimum age (years): 25
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: OTHER

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.

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)

Eligibility 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

Primary outcomes:
measure: Verbal Learning Memory Test Long Delayed Recall (Trial 7)
timeFrame: 6 months post ICU
Secondary outcomes:
measure: Verbal Learning Memory Test, German Version
timeFrame: For patient groups: 6 months; for Healthy Controls: Baseline
measure: Verbal Learning Memory Test, German Version
timeFrame: For patient groups: 12 months; for Healthy Controls: 6 months
measure: Wechsler Memory Scale IV Visual Recall I and II
timeFrame: For patient groups: 6 months; for Healthy Controls: Baseline
measure: Wechsler Memory Scale IV Visual Recall I and II
timeFrame: For patient groups: 12 months; for Healthy Controls: 6 months
measure: Wechsler Memory Scale Digit-Span
timeFrame: For patient groups: 6 months; for Healthy Controls: Baseline
measure: Wechsler Memory Scale Digit-Span
timeFrame: For patient groups: 12 months; for Healthy Controls: 6 months
measure: German Vocabulary Test
timeFrame: For patient groups: 6 months; for Healthy Controls: Baseline
measure: German Vocabulary Test
timeFrame: For patient groups: 12 months; for Healthy Controls: 6 months
measure: Symbol Digit Modalities Test
timeFrame: For patient groups: 6 months; for Healthy Controls: Baseline
measure: Symbol Digit Modalities Test
timeFrame: For patient groups: 12 months; for Healthy Controls: 6 months
measure: Trail Making Test A & B
timeFrame: For patient groups: 6 months; for Healthy Controls: Baseline
measure: Trail Making Test A & B
timeFrame: For patient groups: 12 months; for Healthy Controls: 6 months
measure: Phonetic and Lexical Verbal Fluency
timeFrame: For patient groups: 6 months; for Healthy Controls: Baseline
measure: Phonetic and Lexical Verbal Fluency
timeFrame: For patient groups: 12 months; for Healthy Controls: 6 months
measure: Patient Health Questionnaire Subtests Depression, Anxiety and Somatic Symptoms
timeFrame: For patient groups: 6 months; for Healthy Controls: Baseline
measure: Patient Health Questionnaire Subtests Depression, Anxiety and Somatic Symptoms
timeFrame: For patient groups: 12 months; for Healthy Controls: 6 months
measure: Post-Traumatic Stress Syndrome 10
timeFrame: For patient groups: 6 months; for Healthy Controls: Baseline
measure: Post-Traumatic Stress Syndrome 10
timeFrame: For patient groups: 12 months; for Healthy Controls: 6 months
measure: European Quality of Life 5 Dimensions-5 Levels
timeFrame: For patient groups: 6 months; for Healthy Controls: Baseline
measure: European Quality of Life 5 Dimensions-5 Levels
timeFrame: For patient groups: 12 months; for Healthy Controls: 6 months
measure: Functional Activities Questionnaire
timeFrame: For patient groups: 6 months; for Healthy Controls: Baseline
measure: Functional Activities Questionnaire
timeFrame: For patient groups: 12 months; for Healthy Controls: 6 months
measure: modified version of Rankin Scale Structured Interview (modified for ICU patients)
timeFrame: For patient groups: 6 months; for Healthy Controls: Baseline
measure: modified version of Rankin Scale Structured Interview (modified for ICU patients)
timeFrame: For patient groups: 12 months; for Healthy Controls: 6 months
measure: Pittsburgh Sleep Quality Index
timeFrame: For patient groups: 6 months; for Healthy Controls: Baseline
measure: Pittsburgh Sleep Quality Index
timeFrame: For patient groups: 12 months; for Healthy Controls: 6 months
measure: Mini Mental Status Examination
timeFrame: For patient groups: (OP Probands 1-28 d before OP, 6 months; for Healthy Controls: Baseline
measure: Mini Mental Status Examination
timeFrame: For patient groups: 12 months; for Healthy Controls: 6 months
measure: Clinical Scales at ICU
timeFrame: For Patients during ICU Stay (Day 0, [Day 7 if still on ICU], Day of Release)
measure: Neurological Examination
timeFrame: For patient groups: 6 months, 12 months; for Healthy Controls: Baseline and 6 months
measure: resting state electroencephalogram
timeFrame: For patient groups: 6 months, 12 months; for Healthy Controls: Baseline and 6 months
measure: MRI (3 Tesla) of brain with hippocampus as Region of Interest
timeFrame: For patient groups: 6 months, 12 months; for Healthy Controls: Baseline and 6 months
measure: Blood Sample
timeFrame: For Patient Groups 2-3 samples during ICU, 3-4 Months, 6 months, 12 Months
measure: Lumbar Puncture (voluntary)
timeFrame: 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
Other outcomes:
Locations:
city: Bonn
country: Germany
facility: Department of Anesthesiology, University Hospital Bonn
state: North Rhine-Westphalia (NRW)
city: Bonn
country: Germany
facility: DZNE Center for Clinical Research
state: Northrhine-Westphalia
Study officials:
affiliation: German Center for Neurodegenerative Diseases (DZNE)
name: Michael T Heneka, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: Department of Anesthesiology and Intensive Care Medicine, University Hospital Bonn
name: Andreas Hoeft, M.D.
role: STUDY_CHAIR
affiliation: Research Unit Pulmonary Dysfunction and Sepsis, Department of Anesthesiology and Intensive Care Medicine, University Hospital Bonn
name: Christian Putensen, M.D.
role: STUDY_CHAIR
affiliation: German Center for Neurodegenerative Diseases (DZNE)
name: Thomas Klockgether, M.D.
role: STUDY_CHAIR
References:
citation: 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.
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.
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.
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.
citation: 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.
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.
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. No abstract available.
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.