Endothelial Injury Mechanism in Elderly Patients Undergoing Major Surgery

Endothelial Injury Mechanism of Cognitive Decline and Intervention Study in Elderly Patients Undergoing Major Surgery

The incidence of postoperative cognitive injury is high in elderly patients, especially after major surgery. The relevant pathophysiological mechanisms are still unclear, and the possible mechanisms that have been proposed so far include inflammation, neurotransmitter imbalance and metabolic disorders. In recent years, clinical studies of acute brain dysfunction after vascular endothelial injury have attracted attention.

Degradation of the endothelial glycocalyx layer and subsequent shedding of its constituents is seen as an early marker of endothelial injury, and may increase vascular permeability.Many preclinical and clinical studies have demonstrated an association between inflammatory cytokines such as TNF-α, IL-1β, IL-6, and IL-10 and glycocalyx degradation biomarkers.

The scholars found evidence of plasma endothelial injury after abdominal open surgery in the elderly. Dexmedetomidine could attenuate stress response such as TNF-α, IL-1β and IL-6. Based on the above evidence, we hypothesize that elderly patients experience inflammatory response secondary to surgical traumatic stress after major surgery, greatly increasing the degree of endothelial injury (heparan sulphate and syndecan-1), reducing brain perfusion while increasing Blood-brain barrier permeability (S100B level), promoting the release of cytokines Interleukin-2(IL-2), Interleukin-6(IL-6), tumor necrosis factor-alpha(TNF-α) ,and vascular endothelial growth factor (VEGF) while reducing brain-derived neurotrophic factor(BDNF) synthesis, then leading to postoperative acute spasm. We would test the hypothesis that can reverse these effects and improve cognitive deficits.

Study Overview

• Status: Completed
• Conditions: Postoperative Cognitive Dysfunction; Endothelial Dysfunction; Blood Brain Barrier Defect
• Intervention / Treatment: Drug: Dexmedetomidine; Drug: Saline

• Study Type: Interventional
• Enrollment (Actual): 464
• Phase: Phase 4

Contacts and Locations

Study Locations

• China
  • Anhui
    • Hefei, Anhui, China
      • The First Affiliated Hospital of Anhui Medical University
  • Zhejiang
    • Hangzhou, Zhejiang, China
      • Hangzhou Cancer Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 65 years to 90 years (Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Written informed consent;
2. Patients undergoing selective major gastrointestinal surgery with laparoscope and general anesthesia;
3. Age 65-90 yrs;
4. Anesthesia Society of American (ASA) Scale II~IV;
5. Anticipated surgery time 2-6 hrs;

Exclusion Criteria:

1. Dementia patients（Mini-mental state examination< 20）
2. Factors existed that affect cognition assessment such as language,visual,and auditory dysfunction；
3. Unstable metal status and mental disease；
4. A hematocrit value less than 28%in perioperative period;
5. Patients with abnormal preoperative inflammatory indicators（Higher white blood cell and C-reactive protein);
6. Patients undergoing cardiac and neural surgery;
7. Parkinson's Disease；
8. Sure or suspected abuse of analgesic and sedation drug.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dexmedetomidine; 0.5μg/kg Dexmedetomidine as initial loading dose is given for 15 minutes before induction of anesthesia, followed by a maintenance infusion of 0.4μg/kg/h and stopped 30 minutes before the surgery over.	Drug: Dexmedetomidine; 0.5μg/kg Dexmedetomidine as initial loading dose is given for 15 minutes before induction of anesthesia, followed by a maintenance infusion of 0.4μg/kg/h and stopped 30 minutes before the surgery over.
Placebo Comparator: Controlled; 0.5μg/kg Saline as initial loading dose is given for 15 minutes before induction of anesthesia, followed by a maintenance infusion of 0.4μg/kg/h and stopped 30 minutes before the surgery over.	Drug: Saline; 0.5μg/kg saline as initial loading dose is given for 15 minutes before induction of anesthesia, followed by a maintenance infusion of 0.4μg/kg/h and stopped 30 minutes before the surgery over.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The change of incidence of postoperative delirium	Through CAM-ICU to assess the incidence of the postoperative delirium.	The 1st, 2nd and 7th day after the surgery.
The change of incidence of postoperative cognition dysfunction	The neuropsychological tests performed at the day before the surgery, the 3rd and 7th day after the surgery respectively.Calculate the difference(ΔX) between the score obtained before surgery and 3 or 7 days after the surgery (there are both positive and negative, we use the absolute value), with this difference( ΔX) divided by the standard deviation（SD）of the difference of the normal population, that is ΔX / SD and it is the Z score.If a patient has two or more than two of the absolute value of Z scores ≥1.96, the postoperative cognition dysfunction(POCD) is exist.	1 day Before surgery,the 3rd,7th day after the surgery.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
endothelial injury levels	Plasma of patients was collected to test heparan sulphate and syndecan-1.	1 day Before surgery,the 1st, 2nd, 3rd,7th day after the surgery.
Blood-brain barrier permeability	Plasma of patients was collected to test S100B level	1 day Before surgery,the 1st, 2nd, 3rd,7th day after the surgery.
The serum concentrations of BDNF	Serum level of brain-derived neurotrophic factor (BDNF) was measured.	1 day Before surgery,the 1st, 2nd, 3rd,7th day after the surgery.
Inflammatory factor	Plasma of patients was collected to test cytokines IL-2, IL-6, TNF-α and VEGF level.	1 day Before surgery,the 1st, 2nd, 3rd,7th day after the surgery.

Collaborators and Investigators

• Sponsor: The First Affiliated Hospital of Anhui Medical University
• Collaborators: Hangzhou Cancer Hospital
• Investigators: Principal Investigator: Xinqi Cheng, PhD, The First Affiliated Hospital of Anhui Medical University

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2019
• Primary Completion (Actual): October 30, 2020
• Study Completion (Actual): October 31, 2020

Study Registration Dates

• First Submitted: August 13, 2018
• First Submitted That Met QC Criteria: August 17, 2018
• First Posted (Actual): August 21, 2018

Study Record Updates

• Last Update Posted (Actual): February 10, 2021
• Last Update Submitted That Met QC Criteria: February 7, 2021
• Last Verified: September 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Pathologic Processes; Postoperative Complications; Neurocognitive Disorders; Cognition Disorders; Cognitive Dysfunction; Postoperative Cognitive Complications; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Non-Narcotic; Adrenergic alpha-2 Receptor Agonists; Adrenergic alpha-Agonists; Adrenergic Agonists; Hypnotics and Sedatives; Dexmedetomidine
• Other Study ID Numbers: 7742

Drug and device information, study documents

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