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Modulating Surgery-Induced Blood-Brain Barrier Disruption in Elderly

Primary Purpose

Delirium, Postoperative

Status
Not yet recruiting
Phase
Not Applicable
Locations
Study Type
Interventional
Intervention
Dexmedetomidine Injection [Precedex]
Lidocaine IV
normal saline
Sponsored by
Samsung Medical Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Delirium, Postoperative focused on measuring Postoperative delirium, dexmedetomidine, lidocaine, neuroinflammation, CPAR, blood brain barrier

Eligibility Criteria

65 Years - undefined (Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: American Society of Anesthesiologists (ASA) physical status classification I-III Undergoing elective open pancreatoduodenectomy Voluntary participation in the trial and signed informed consent Exclusion Criteria: Sinus bradycardia (heart rate (HR) <50 beats per minute (bpm)), Adams-Stokes syndrome, sick sinus or Wolff-Parkinson-White syndrome, or second-degree trioventricular block and over. Concurrent treatment with a class 1 antiarrhythmic or amiodarone) History of hypersensitivity reactions or contraindications to the study drugs (dexmedetomidine or lidocaine). Patient at personal of familial risk of malignant hyperthermia and porphyria Body mass index (BMI) ˃40 kg/m2 Patients with coagulopathy (INR 1.5 or more, platelet count less than 75000/ul) or other contraindications to spinal tapping, or on anticoagulants that would preclude safe lumbar punctures. History of severe hepatic (Childs-Pugh Score > Class A ) or renal (glomerular filtration rate <30m)/min×1.73m2) disorders. Severe audio-visual impairments, or inability to speak precluding communication. Evidence of preoperative delirium (Confusion Assessment Method, CAM) History of uncontrolled seizures. Patients on immunosuppressants (e.g., steroids) or immunomodulatory therapy, chemotherapeutic agents with known cognitive effects. Patients taking the following drugs that are moderate-strong inhibitors of the CYP1A2 and CYP3A4 metabolic pathways within 72 hours prior to surgery

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm 3

    Arm Type

    Experimental

    Experimental

    Placebo Comparator

    Arm Label

    Dexmedetomidine group

    Lidocaine group

    Control group

    Arm Description

    Patients in the dexmedetomidine group will be administered a bolus of 0.3 ug/kg intravenous dexmedetomidine over 10 min before anesthetic induction. After bolus injection, a continuous infusion of 0.3 ug/kg/hr of intravenous dexmedetomidine will be administered until the end of surgery.

    Patients in the lidocaine group will receive a bolus of 1.5 mg/kg intravenous lidocaine over 10 min before induction of anesthesia. A continuous infusion of 1.5 mg/kg/hour of systemic lidocaine will be administered until the end of the surgery.

    Patients in the control group will be administered equal volumes of 0.9% saline using the identical application scheme.

    Outcomes

    Primary Outcome Measures

    Postoperative change of cerebrospinal-plasma albumin ratio (CPAR)
    The change of CPAR will be calculated. CPAR was calculated using the formula 1000 x (CSF albumin (mg/dl))/(serum albumin (mg/dl).

    Secondary Outcome Measures

    The changes of inflammatory biomarker level in blood
    IL-6
    The changes of neuronal damage biomarker level in blood
    neuron specific enolase
    The changes of inflammatory, neuronal damage, BBB permeability biomarker level in blood
    sb100 protein
    The incidence of postoperative delirium
    Intensive Care Unit (CAM-ICU) and 3-min diagnostic interview for CAM (3D-CAM) for ICU patients and ward patients, respectively
    The subtype of postoperative delirium
    hyperactive, hypoactive or mixed type will be defined by RASS score
    Delirium Rating Scale Revised (DRS-R-98)
    The severity of delirium will be assessed using the Delirium Rating Scale Revised (DRS-R-98)
    Onset and duration of delirium
    Intensive Care Unit (CAM-ICU) and 3-min diagnostic interview for CAM (3D-CAM)
    Pain score (NRS)
    The degree of surgical pain will be assessed at rest, when taking a deep breath, and when moving by NRS.
    Subjective sleep quality
    the NRS (an 11-point scale where 0 = the best sleep, and 10 = the worst sleep) once daily
    Montreal cognitive Assessment (MoCA)
    Cognitive assessment
    Ideal outcome of pancreatoduodenectmoy
    defined by the absence of In-hospital mortality, Severe complications (Clavien Dindo ≥3), Postoperative pancreatic fistula - ISGPS Grade B/C, Reoperation, Length of stay >75th percentile, or Readmission
    non-delirium complications within 30 days after surgery
    The severity of non-delirium complications are graded using Clavien-Dindo classification

    Full Information

    First Posted
    October 3, 2023
    Last Updated
    October 15, 2023
    Sponsor
    Samsung Medical Center
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    1. Study Identification

    Unique Protocol Identification Number
    NCT06090955
    Brief Title
    Modulating Surgery-Induced Blood-Brain Barrier Disruption in Elderly
    Official Title
    Modulating Surgery-Induced Blood-Brain Barrier Disruption in Elderly: Impact of Dexmedetomidine and Lidocaine, a Randomized Controlled Trial
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    October 2023
    Overall Recruitment Status
    Not yet recruiting
    Study Start Date
    October 2023 (Anticipated)
    Primary Completion Date
    November 30, 2024 (Anticipated)
    Study Completion Date
    December 31, 2024 (Anticipated)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Principal Investigator
    Name of the Sponsor
    Samsung Medical Center

    4. Oversight

    Studies a U.S. FDA-regulated Drug Product
    No
    Studies a U.S. FDA-regulated Device Product
    No
    Product Manufactured in and Exported from the U.S.
    No
    Data Monitoring Committee
    Yes

    5. Study Description

    Brief Summary
    Postoperative delirium (POD) is the most common complications (~50-60%) in elderly and major challenges to our rapidly growing aging population. Growing evidence suggests a possible role for neuroinflammation in the development of delirium, which is facilitated by a transient increase in blood-brain barrier (BBB) permeability. Lidocaine and dexmedetomidine, commonly used anesthetic adjuncts, have anti-inflammatory properties. Both drugs are reported to have modulatory effect on the intergrity of BBB and associated with a beneficial effect on postoperative neurocognitive dysfunction. In this regard, The investigators aimed to prospectively compare the modulatory effect of the intraoperative administration of dexmedetomidine or lidocaine with a sham control group (normal saline solution) on surgery-induced BBB disruption.
    Detailed Description
    Postoperative delirium (POD) negatively affects cognitive domains including memory, attention, and concentration after surgery. The incidence of POD in high-risk populations, such as aged, patients in intensive care units (ICU) and with previous cognitive impairment, the incidence of POD is as high as 50 to 60%. POD is associated with increased morbidity, mortality, and health-care costs. The 1-year survival probability is reduced by approximately 10% for each additional day of POD. Additionally, it is closely related to long-lasting postoperative cognitive dysfunction. Surgical trauma activates the innate immune system and central nervous system (CNS) is influenced by surgical trauma by inflammatory mediators rapidly reaching the brain, which is facilitated by a transient increase in blood-brain barrier (BBB) permeability. Recent neuroimaging studies demonstrated BBB dysfunction in patients with delirium after cardiac surgery. The biomakers indicative of BBB breakdown were recently associated with the onset and intensity of delirium. These findings imply that the BBB could serve as a pivotal interface in regulating neuroinflammation and cognitive deterioration following surgical procedures. Dexmedetomidine and lidocaine are increasingly used as part of a multimodal intraoperative anesthetic adjunct in a variety of surgical procedures. Dexmedetomidine, as a highly selective central presynaptic α2-adrenergic agonist, has sedative, sympatholytic and anti-inflammatory effects. Perioperative dexmedetomidine administration reduced delirium incidence by up to 50% and duration by 0.7 days in surgical populations. Lidocaine, an amide local anesthetic and class-1 antiarrhythmic agent, also has anti-inflammatory and opiate-sparing effects, accelerating gastrointestinal recovery and reducing hospital length of stay. In addition, previous clinical researches have suggested a beneficial effect of perioperative systemic lidocaine on postoperative neurocognitive dysfunction. Although both drugs alleviate surgery-induced systemic inflammation and animal models have indicated a potential protective effect of these agents against surgery-induced disruption of the BBB, few studies have examined the role of these different anesthetics in the interplay between peripheral and central inflammation in human subjects. In this regard, this study aimed to prospectively compare the modulatory effect of the intraoperative administration of dexmedetomidine or lidocaine with a sham control group (normal saline solution) on surgery-induced BBB disruption in a randomized, placebo-controlled, double-blind, triple-parallel clinical trial. The primary outcome measure was "cerebrospinal-plasma albumin ratio (CPAR)", which is a gold standard measure for BBB permeability, presenting in vivo evidence for the physical breakdown of the blood-CSF barrier in human. The investigators hyptothesized that the use of intraoperative continuous infusion of dexmedetomidine or lidocaine would be statistically superior to placebo control in preserving BBB integrity.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Delirium, Postoperative
    Keywords
    Postoperative delirium, dexmedetomidine, lidocaine, neuroinflammation, CPAR, blood brain barrier

    7. Study Design

    Primary Purpose
    Prevention
    Study Phase
    Not Applicable
    Interventional Study Model
    Parallel Assignment
    Masking
    ParticipantCare ProviderInvestigatorOutcomes Assessor
    Allocation
    Randomized
    Enrollment
    108 (Anticipated)

    8. Arms, Groups, and Interventions

    Arm Title
    Dexmedetomidine group
    Arm Type
    Experimental
    Arm Description
    Patients in the dexmedetomidine group will be administered a bolus of 0.3 ug/kg intravenous dexmedetomidine over 10 min before anesthetic induction. After bolus injection, a continuous infusion of 0.3 ug/kg/hr of intravenous dexmedetomidine will be administered until the end of surgery.
    Arm Title
    Lidocaine group
    Arm Type
    Experimental
    Arm Description
    Patients in the lidocaine group will receive a bolus of 1.5 mg/kg intravenous lidocaine over 10 min before induction of anesthesia. A continuous infusion of 1.5 mg/kg/hour of systemic lidocaine will be administered until the end of the surgery.
    Arm Title
    Control group
    Arm Type
    Placebo Comparator
    Arm Description
    Patients in the control group will be administered equal volumes of 0.9% saline using the identical application scheme.
    Intervention Type
    Drug
    Intervention Name(s)
    Dexmedetomidine Injection [Precedex]
    Other Intervention Name(s)
    Dex
    Intervention Description
    The study drugs(dexmedetomidine 80 μg/20 mL) will be prepared with 20 mL syringe and marked as 'trial drug', which are identical in appearance with control and active comparator. In order to avoid anaesthesiologists' speculation about the randomised assignment, the study drugs will be infused at the same rate.
    Intervention Type
    Drug
    Intervention Name(s)
    Lidocaine IV
    Other Intervention Name(s)
    Lido
    Intervention Description
    The study drugs(lidocaine 400 mg/20 mL) will be prepared with 20 mL syringe and marked as 'trial drug', which are identical in appearance with control and active comparator. In order to avoid anaesthesiologists' speculation about the randomised assignment, the study drugs will be infused at the same rate.
    Intervention Type
    Drug
    Intervention Name(s)
    normal saline
    Other Intervention Name(s)
    Control
    Intervention Description
    The study drugs(normal saline) will be prepared with 20 mL syringe and marked as 'trial drug', which are identical in appearance with control and active comparator. In order to avoid anaesthesiologists' speculation about the randomised assignment, the study drugs will be infused at the same rate.
    Primary Outcome Measure Information:
    Title
    Postoperative change of cerebrospinal-plasma albumin ratio (CPAR)
    Description
    The change of CPAR will be calculated. CPAR was calculated using the formula 1000 x (CSF albumin (mg/dl))/(serum albumin (mg/dl).
    Time Frame
    From the baseline to immediate postoperative values
    Secondary Outcome Measure Information:
    Title
    The changes of inflammatory biomarker level in blood
    Description
    IL-6
    Time Frame
    From the baseline to immediate postoperative state and postoperative day 2
    Title
    The changes of neuronal damage biomarker level in blood
    Description
    neuron specific enolase
    Time Frame
    From the baseline to immediate postoperative state and postoperative day 2
    Title
    The changes of inflammatory, neuronal damage, BBB permeability biomarker level in blood
    Description
    sb100 protein
    Time Frame
    From the baseline to immediate postoperative state and postoperative day 2
    Title
    The incidence of postoperative delirium
    Description
    Intensive Care Unit (CAM-ICU) and 3-min diagnostic interview for CAM (3D-CAM) for ICU patients and ward patients, respectively
    Time Frame
    From postoperative day 0 to 5
    Title
    The subtype of postoperative delirium
    Description
    hyperactive, hypoactive or mixed type will be defined by RASS score
    Time Frame
    From postoperative day 0 to 5
    Title
    Delirium Rating Scale Revised (DRS-R-98)
    Description
    The severity of delirium will be assessed using the Delirium Rating Scale Revised (DRS-R-98)
    Time Frame
    From postoperative day 0 to 5
    Title
    Onset and duration of delirium
    Description
    Intensive Care Unit (CAM-ICU) and 3-min diagnostic interview for CAM (3D-CAM)
    Time Frame
    From postoperative day 0 to 5
    Title
    Pain score (NRS)
    Description
    The degree of surgical pain will be assessed at rest, when taking a deep breath, and when moving by NRS.
    Time Frame
    From postoperative day 0 to 5
    Title
    Subjective sleep quality
    Description
    the NRS (an 11-point scale where 0 = the best sleep, and 10 = the worst sleep) once daily
    Time Frame
    From postoperative day 0 to 5
    Title
    Montreal cognitive Assessment (MoCA)
    Description
    Cognitive assessment
    Time Frame
    at baseline and 7 days after surgery or at discharge
    Title
    Ideal outcome of pancreatoduodenectmoy
    Description
    defined by the absence of In-hospital mortality, Severe complications (Clavien Dindo ≥3), Postoperative pancreatic fistula - ISGPS Grade B/C, Reoperation, Length of stay >75th percentile, or Readmission
    Time Frame
    postoperative day 30
    Title
    non-delirium complications within 30 days after surgery
    Description
    The severity of non-delirium complications are graded using Clavien-Dindo classification
    Time Frame
    Within 30 days after surgery

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    65 Years
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    Inclusion Criteria: American Society of Anesthesiologists (ASA) physical status classification I-III Undergoing elective open pancreatoduodenectomy Voluntary participation in the trial and signed informed consent Exclusion Criteria: Sinus bradycardia (heart rate (HR) <50 beats per minute (bpm)), Adams-Stokes syndrome, sick sinus or Wolff-Parkinson-White syndrome, or second-degree trioventricular block and over. Concurrent treatment with a class 1 antiarrhythmic or amiodarone) History of hypersensitivity reactions or contraindications to the study drugs (dexmedetomidine or lidocaine). Patient at personal of familial risk of malignant hyperthermia and porphyria Body mass index (BMI) ˃40 kg/m2 Patients with coagulopathy (INR 1.5 or more, platelet count less than 75000/ul) or other contraindications to spinal tapping, or on anticoagulants that would preclude safe lumbar punctures. History of severe hepatic (Childs-Pugh Score > Class A ) or renal (glomerular filtration rate <30m)/min×1.73m2) disorders. Severe audio-visual impairments, or inability to speak precluding communication. Evidence of preoperative delirium (Confusion Assessment Method, CAM) History of uncontrolled seizures. Patients on immunosuppressants (e.g., steroids) or immunomodulatory therapy, chemotherapeutic agents with known cognitive effects. Patients taking the following drugs that are moderate-strong inhibitors of the CYP1A2 and CYP3A4 metabolic pathways within 72 hours prior to surgery
    Central Contact Person:
    First Name & Middle Initial & Last Name or Official Title & Degree
    jeayoun kim
    Phone
    +821039268786
    Email
    kimjy0705@naver.com
    Overall Study Officials:
    First Name & Middle Initial & Last Name & Degree
    Jiseon Jeong
    Organizational Affiliation
    Samsung Medical Center
    Official's Role
    Principal Investigator

    12. IPD Sharing Statement

    Plan to Share IPD
    No
    IPD Sharing Plan Description
    Study data may be made available on request to the principal investigators with an appropriate research and data-protection plan agreed on.

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    Modulating Surgery-Induced Blood-Brain Barrier Disruption in Elderly

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