Research Area E - Long-term Sequelae
Recent advances in Critical Care have led to a marked decline of mortality in the intensive care unit and, in consequence, to increasing numbers of survivors of severe sepsis. Many of these patients, who have survived the initial acute burst of the disease, suffer from multiple sequelae for the rest of their lives.
Beyond detrimental consequences that arise directly from the shutdown of multiple organs/ functions, most sepsis survivors feature neurological, psychological, cognitive, immunological, and endocrinological impairments that can severely compromise life quality. Moreover, long-term sequelae of sepsis result in greater healthcare utilization and increased mortality of long-term survivors. Despite a steadily increasing general awareness of the clinical relevance of sepsis as a whole, efforts to shed light on the nature and causes of associated long-term sequelae have hitherto markedly lagged behind. It is thus not surprising that even some of the most basic questions concerning the post-acute phase of the disease remain obscure. Research area E aims to close this knowledge gap by investigating causes and characteristics of a wide range of features of the post-acute phase of sepsis. These include neuromuscular weakness, cognitive impairment, depression, posttraumatic stress disorder, pulmonary dysfunction, dysphagia, and the currently hotly debated issue of immune suppression. Our long-term goal is to identify pragmatic diagnostic criteria, modifiable risk factors, and rational therapy options in order to improve or complement current long-term therapy and rehabilitation regimes. Therefore, research area E is a composite of basic and clinical research units. Sepsis-associated immune suppression is one major topic in this field that is dealt with by the projects Recuperate, Anergy and Loss. NeuroSOS-Nerve and NeuroSOS-CIP investigate sepsis-induced neuromuscular weakness (i.e. critical illness polyneuropathy and critical illness myopathy) in the acute phase of sepsis but also in the long-time follow up. NeuroSOS-Dysphagia focuses on problems related to dysphagia and malnutrition in the course of sepsis. Septic encephalopathy and sepsis-induced cognitive disturbances are the topic of the Groups NeuroSOS-Enc and Loss-Cog-Train. In addition, the project NeuroSOS-Sync studies oscillatory processing in the brain to identify residual neurocognitive and functional impairments after recovery from severe sepsis. Finally, Smooth, Crisis and Neuro Pain focus on aspects of impairments of quality of life and psychological sequelae of sepsis.
Projects in Research Area E
Anergy
T-cell paralysis in sepsis
I. Rubio
Crisis
Stress disorders following critical illness in patients with severe sepsis (clinical trial)
G.-B. Wintermann, J. Rosendahl
HTTS
Systemic vs. local inflammation: Analysis of tonsillar T-cell function as a surrogate marker of the immune status in Sepsis vs. chronic tonsillitis (clinical trial)
K. Geißler
Loss
Long-term Immunological Sequelae in Sepsis-Survivors (clinical trial)
K. Ferrari-Kühne
Loss-Cog MRI
Long-term Sequelae of Severe Sepsis: Cognitive Impairment and Structural Brain Alterations - an MRI study (clinical trial)
T. Götz
Loss-Cog-Train
Long-term Cognitive and Functional Outcome of Survivors of Severe Sepsis following a computerized Cognitive Training
Acronym: Loss-Cog-Train
Principal Investigator: Prof. Dr. Farsin Hamzei
Research Area: E Long-term Sequelae
Project Number: E5.2
Duration: 01.07.2012 - 30.06.2015
Module: In-house Professorship Group
The Problem
Cognitive deficits have been described several years after an event of sepsis. The aim of this multicenter randomized controlled trial is to investigate the long-term effect of a computer-based cognitive training in severe sepsis survivors.
Preparative work for the funding period and working plan
Different aspects of cognition, like alertness, memory, visual constructive function, executive cognitive function and speech will be evaluated. The scores of each test are normalized by using gender, education and age specific values and expressed in percent of the normal status. A “Global Index Score” will be calculated as mean of the individual test scores. These tests will be evaluated at time point t0 (= at time point of admission to the post-acute rehabilitation centers) and six weeks after admission to the rehabilitation centers (t1). At this time point, patients will be screened for eligibility, and randomized to intervention group (IG) and control group (CG). We expect that three months of cognitive training in IG will improve cognitive function in comparison to CG. Cognitive function and functional disability will be evaluated in IG and CG a three months after randomization (t2 = immediately after the end of intervention) in order to demonstrate short-term effects of therapy and 12 months after randomization to assess long term effects of therapy (= t3).
Contact
Tel. +49 (0)36601 - 49 471
Moritz Klinik GmbH & Co. KG
Hermann-Sachse-Straße 46
07639 Bad Klosterlausnitz
MDSC-iRESP
Evaluation of Functional Interaction between Myeloid-derived Suppressor Cells and Immune Response of Sepsis Patients (clinical trial)
L. Rump, K. Ferrari-Kühne
NeuroPain
Neurological sequelae and changes in nociception after severe sepsis or septic shock (clinical trial)
W. Meißner, A. Günther
NeuroSOS-Dysphagia
Neurological Sequelae of Sepsis (NeuroSOS-DYSPHAGIA): Chronic dysphagia in patients with critical illness polyneuropathy (CIP) or myopathy (CIM) (clinical trial)
J. Zielske
NeuroSOS-Enc
Synaptic transmission dysfunction in experimental septic encephalopathy
Acronym: NeuroSOS-Enc
Principal Investigator: Prof. Dr. Christian Geis
Team: Benedikt Grünewald, Holger Haselmann
Research Area: E Long-term Sequelae
Project Number: E3.3
Duration: 01.07.2012 - 30.06.2015
Module: In-house Professorship Group
The Problem
Encephalopathy is a common neurological complication in patients with sepsis, but the underlying pathophysiological mechanisms are only rudimentarily understood. Here, we aim to elucidate the disturbances of synaptic signalling which cause cognitive and memory deficits with electrophysiological methods and high-resolution imaging techniques.
Results so far
In this project, a multifaceted experimental approach is applied to understand synaptic pathology leading to the symptoms of septic encephalopathy (SE). First, we perform neurophysiological and morphological studies in brain slices obtained from mice after experimental SE. We established the paradigms to analyze changes in synaptic long-term plasticity by recording field potentials or by single cell patch-clamp recording in the hippocampus. Using high-resolution microscopy, we are able to study disturbances in the synaptic architecture of animals with SE. In the next step, we will evaluate the role of tumor necrosis alpha (TNF) in the development of SE. Therefore, we will use genetic and pharmacological methods in the mouse model of SE and test for behavioral, morphological and neurophysiological changes. Furthermore, we will investigate the pathogenic potential of SE patient cerebrospinal fluid (CSF). We will analyze patient CSF samples for the expression pattern of proinflammatory mediators, injury marker and neurotransmitters and test pooled samples in-vivo in an innovative passive-transfer model. Therefore, we established an animal model with implanted intrathecal catheters. Patient CSF can be applied directly to the subarachnoidic space, either by single injection or chronically, and the behavior of the recipient animals can be monitored. Electrophysiological and morphological studies can be performed at the end of the experiment after preparing hippocampal brain slices.
Contact
Tel.: +49 (0)3641 - 9 32 34 01
Universitätsklinikum Jena
Hans-Berger-Klinik für Neurologie
Am Klinikum 1
07747 Jena
NeuroSOS-Nerve/CIP
Neurological Sequelae of Sepsis (clinical trial)
H. Axer
Recuperate
Reconstitution of immunity in sepsis survivors
Acronym: Recuperate
Principal Investigator: Prof. Dr. med. Thomas Kamradt
Research Area: E Long-term Sequelae
Project Number: E1.3
Duration: 01.07.2012 - 30.06.2015
Module: In-house Professorship Group
The Problem
The duration, cellular and molecular correlates and the clinical consequences of sepsis-induced immunodeficiency are unknown. This proposal aims at elucidating the cellular and molecular mechanisms and the consequences of sepsis-induced immunodeficiency beyond the acute phase of the disease and strategies for future therapeutic interventions.
Contact
Tel. +49 (0)3641 - 9 38 780
Universitätsklinikum Jena
Institut für Immunologie
Leutragraben 3
07743 Jena
Regeffect
Phenotypical and Functional Delineation of Regulatory T Cell Subpopulations and their Effect on Lymphocyte Activation and Effector Function in Sepsis (clinical trial)
K. Ferrari-Kühne
SepMech
Long-term impact of Sepsis-associated Encephalopathy: Mechanisms and therapeutic options
Acronym: SepMech
Principal Investigator: Dr. Silvio Schmidt
Team: Marcus Böhme
Research Area: E Long-term Sequelae
Project Number: E3.2
Duration: 01.05.2011 - 30.04.2013
Module: Start-up Scientist
The Problem
Survivors of severe sepsis often suffer from cognitive impairments and emotional disturbances like depression and anxiety, which is a serious and debilitating long-term consequence of sepsis. This imposes a growing socioeconomic burden as it affects the independence in daily life, competence in profession, quality of life, and social participation. Brain dysfunctions underlying these long-term impairments are believed to be diffusely distributed but the pathophysiology remains unclear.
Results so far
Based on the general relationship between functional and structural alterations, the combination of repeated structural MRI and Deformation Based Morphometry (DBM) is used to screen the whole brain regarding structural changes and to identify brain regions especially vulnerable to sepsis.
Severe sepsis was induced in rats by peritoneal injection of LPS (lipopolysaccharides) to reach a 50% survival of the septic rats. Severity scores worsened continuously over time reaching maximum between 18 and 24 h, and then survivors recovered to baseline levels in the following 4 days. Three-dimensional MRI was performed before as well as 1, 2, 4, 8 and 12 weeks after sepsis induction. The DBM analysis revealed a pattern of temporal volume changes strongest pronounced as tissue shrinkage in the amygdala. Here, bilateral volume loss by around 12% persisted up to two weeks and then recovered to control values following 12 weeks. In parallel to morphologic changes in the amygdala, the behavioural reactivity to a stressful situation was disturbed in the same time-scale as analyzed using the open-field task.
These preliminary results highlight extensive physical stress and limbic structures as central players mediating cognitive and emotional disturbances following sepsis. We hypothesize that our finding constitutes the morphological equivalent of a post-sepsis stress disorder (PSSD). Our novel hypothesis is now tested by speciἀc behavioural experiments and histological investigations using the LPS and additionally the peritoneal contamination and infection model (PCI).
Contact
Tel.: +49 (0)3641 - 9 32 59 00
Universitätsklinikum Jena
Hans-Berger-Klinik für Neurologie
Experimentelle Neurologie
Forschungszentrum Lobeda
Am Klinikum 1
07747 Jena
Smooth
Sepsis survivors monitoring and coordination in outpatient health care (clinical trial)
J. Gensichen, K. Schmidt
TPHS
Satellite Project of ANERGY: T-cell paralysis in human Sepsis (clinical trial)
F. Borken, I. Rubio