Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT03055325 |
| Other study ID # |
POSINI |
| Secondary ID |
|
| Status |
Completed |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
January 1, 2017 |
| Est. completion date |
December 31, 2023 |
Study information
| Verified date |
January 2024 |
| Source |
Karolinska University Hospital |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
The aim is to map the inflammatory response after surgery and further investigate the
mechanisms by which inflammation is regulated. The inflammatory cascade is pivotal in
protecting organisms against invading pathogens and in enabling healing of damaged tissues,
yet the cascade itself may be harmful to the organism when excessive (e g septic chock).
The increased immune-reactivity after trauma, such as surgery, is furthermore associated with
post-operative declines in memory and learning capacity, a condition likely related to the
notion of "sickness behavior". The effects on the brain after surgery and the associated
neuro-immune crosstalk will now be investigated with focus on changes in immune reactivity in
peripheral blood after surgery.
Description:
Surgical trauma causes release of damage-associated molecular patterns (DAMPs) and other
alarmines (e.g. high mobility group box (HMGB-1)) targeting receptors on local cells of the
innate immune system, such as macrophages. This cellular response to trauma is followed by a
rapid release of an array of inflammatory mediators (e.g. tumor necrosis factor alfa (TNFa),
interleukin (IL)-1B, IL-6, IL-8, IL-10) being dependent on intracellular activation of
nuclear factor nuclear factor kappa beta (NF-kB). Until recently it was believed that the
brain is protected from this cascade of inflammatory mediators primarily due to an intact
blood-brain-barrier (BBB). However, there is now a growing body of evidence that long term
impairment of brain functions is associated with trauma-induced activation of the brain
innate immune system with subsequent impairment of higher cognitive processes and risk for
later permanent dementia. Yet, the link between systemic inflammation and cognitive
impairment is not fully understood.
A recent study has mapped periphery-to-brain-signaling after surgical trauma and the impact
of major surgical trauma on the human brain by serial positron emission tomography
(PET)-imaging. In series of surgical patients, profound and biphasic changes in brain immune
activity after surgery has been demonstrated after major abdominal surgery with signs of
early depression followed by an increased immune activity at 3 months postoperatively. These
biphasic changes in brain immunity seem to be aligned with simultaneous changes in whole
blood immune reactivity to lipid polysaccharide (LPS) suggesting a close link between brain
and peripheral immune systems in regulation of acute inflammation and immune responses.
Preclinical work in surgical animal models indicates disruption of the BBB with migration of
peripheral macrophages into the brain as a pathway of potential importance. Evidence from an
orthopedic surgery model in mice of trauma-induced altered hippocampal neuro-immune activity
further raises the question whether peripheral markers of neurodegeneration S100b,
neurofilament light (NFL), ptau, beta-amyloid) are associated with postoperative cognitive
dysfunction (POCD).
The immune-regulatory role of the brain via the cholinergic anti-inflammatory reflex pathway
(mediated by the vagal nerve) has been identified as potential target for immune-modulatory
treatment strategies in systemic inflammation. We have moreover demonstrated a distinct
release of human carotid body inflammatory mediators at hypoxia and gene expression related
to inflammatory mediators, suggesting a potential role of the human carotid body in
periphery-to-brain immune-signaling. Modulation of a vagal nerve-derived inflammatory reflex
pathway by electrical stimulation has recently been successfully applied in treatment of
chronic inflammation among patients with rheumatoid arthritis.
The hypothesis is that vagal nerve activity modulates systemic inflammation in patients after
major surgery and that this modulation is associated with cognitive performance in the
postoperative period.
With a more comprehensive understanding of immune-to-brain signaling after surgical trauma
and how this biphasic inflammatory response pattern is regulated by cellular and neuronal
components, the impact of immune modulation on key processes behind surgery-induced brain
dysfunction can be explored, and possible neural and humoral targets for relevant
anti-inflammatory treatments established.
