The White Blood Cell Reactivity Following Surgical Trauma and Associated Regulatory Mechanisms.

Post-surgery Systemic Inflammation and Neuro-immune Interactions

The purpose of this study is to describe numerical and functional changes in the white blood cell efter surgical trauma. Further, observed immune cell changes correlate to heart rate variability and cognitive function will be assessed.

Study Overview

• Status: Completed
• Conditions: Neuroinflammation
• Intervention / Treatment: Other: Cognitive testing, testing of heart rate variability and blood samples

Detailed Description

Surgical trauma causes release of damage-associated molecular patterns (DAMPs) and other alarmines (e.g. 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. TNFα, IL-1B, IL-6, IL-8, IL-10) being dependent on intracellular activation of nuclear factor 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.

Recent studies have mapped periphery-to-brain-signaling after surgical trauma and the impact of major surgical trauma on the human brain by serial 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 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 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.

In abdominal surgery patients we will map inflammatory periphery-to-brain communication by description of the temporal association between brain regulation of peripheral immunity (i.e., temporal changes in vagal nerve activity as measured by serial measurements of heart rate variability), repeated blood reactivity to LPS by serial ex vivo LPS challenge and simultaneous plasma/serum-borne CNS inflammatory and brain injury biomarkers to explore the impact of changes in systemic and brain immune function after surgery on long-term cognitive performance.

• Study Type: Observational
• Enrollment (Actual): 40

Contacts and Locations

Study Locations

• Sweden
  • Stockholm, Sweden
    • Karolinska Universitetssjukhuset Solna

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Probability Sample

Study Population

Patients with diagnosed prostate disease who are scheduled for elective robot assisted prostate surgery (RALP) and who are otherwise healthy, with a BMI below 33 and who score >23 performance points on Mini-mental state examination (MMSE).

Description

INCLUSION CRITERIA

• Diagnosed prostate disease who are scheduled for elective robot assisted prostate surgery (RALP) and who are otherwise healthy
• A body mass index (BMI) below 33
• Mini-mental state examination (MMSE) scoring >23

EXCLUSION CRITERIA

Exclusion criteria are patients with:

• Neurodegenerative disease
• Significant psychiatric illness
• Previous stroke
• Pacemaker, myocardial infarction or cardiac arrhythmias,
• Known obstructive coronary artery disease, left ventricular hypertrophy or New York Heart Association (NYHA) class 2-4 heart failure
• Chronic pain or inflammatory disease such as rheumatoid arthritis, inflammatory bowel disease, SLE, psoriasis
• Steroidal therapy
• Statin medication
• Medication with ß-blockers, anti-cholinergic medication
• Poorly controlled diabetes mellitus or any other condition known to cause autonomic dysfunction
• Abuse of alcohol or drugs
• Previous splenectomy
• Presumed uncooperativeness or legal incapacity.

The patient should not have:

• undergone surgery the last 6 months
• been treated for cancer the last 12 months
• been treated for infectious disease the previous month.

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in subsets of Monocytes after surgical trauma	Changes in subsets of Monocytes after surgical trauma	Up to 6 months after surgery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
T-cell numbers after surgical trauma.	T-cell numbers after surgical trauma.	Up to 6 months after surgery
B-cell numbers after surgical trauma.	B-cell numbers after surgical trauma.	Up to 6 months after surgery
T-cell functionality changes after surgical trauma.	T-cell functionality changes after surgical trauma.	Up to 6 months after surgery
B-cell functionality changes after surgical trauma.	B-cell functionality changes after surgical trauma.	Up to 6 months after surgery

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Genetic response to surgical trauma	Genetic response to surgical trauma, i.e. white blood cell RNA sequencing	Up to 6 months after surgery

Collaborators and Investigators

• Sponsor: Karolinska University Hospital
• Collaborators: Karolinska Institutet
• Investigators: Principal Investigator: Lars I Eriksson, Karolinska University Hospital and Karolinska Institutet

Study record dates

Study Major Dates

• Study Start (Actual): January 31, 2017
• Primary Completion (Actual): December 31, 2022
• Study Completion (Actual): December 31, 2023

Study Registration Dates

• First Submitted: January 13, 2017
• First Submitted That Met QC Criteria: February 15, 2017
• First Posted (Actual): February 20, 2017

Study Record Updates

• Last Update Posted (Actual): January 17, 2024
• Last Update Submitted That Met QC Criteria: January 15, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Inflammation/physiopathology, Immune System/immunology,; Neuroimmunomodulation/physiology, General Surgery; Heart Rate/physiology*Vagus Nerve/physiology*
• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Inflammation; Neuroinflammatory Diseases
• Other Study ID Numbers: POSINI2

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No