Modulating Surgery-Induced Blood-Brain Barrier Disruption in Elderly: Impact of Dexmedetomidine and Lidocaine, a Randomized Controlled Trial
Overview
- Phase
- Not Applicable
- Intervention
- Dexmedetomidine Injection [Precedex]
- Conditions
- Delirium, Postoperative
- Sponsor
- Samsung Medical Center
- Enrollment
- 108
- Locations
- 1
- Primary Endpoint
- Postoperative change of cerebrospinal-plasma albumin ratio (CPAR)
- Status
- Recruiting
- Last Updated
- 2 years ago
Overview
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.
Investigators
Jiseon Jeong
Associate professor
Samsung Medical Center
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.
Arms & Interventions
Dexmedetomidine group
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.
Intervention: Dexmedetomidine Injection [Precedex]
Lidocaine group
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.
Intervention: Lidocaine IV
Control group
Patients in the control group will be administered equal volumes of 0.9% saline using the identical application scheme.
Intervention: normal saline
Outcomes
Primary Outcomes
Postoperative change of cerebrospinal-plasma albumin ratio (CPAR)
Time Frame: From the baseline to immediate postoperative values
The change of CPAR will be calculated. CPAR was calculated using the formula 1000 x (CSF albumin (mg/dl))/(serum albumin (mg/dl).
Secondary Outcomes
- The changes of inflammatory biomarker level in blood(From the baseline to immediate postoperative state and postoperative day 2)
- Montreal cognitive Assessment (MoCA)(at baseline and 7 days after surgery or at discharge)
- Pain score (NRS)(From postoperative day 0 to 5)
- The changes of inflammatory, neuronal damage, BBB permeability biomarker level in blood(From the baseline to immediate postoperative state and postoperative day 2)
- The subtype of postoperative delirium(From postoperative day 0 to 5)
- Onset and duration of delirium(From postoperative day 0 to 5)
- Subjective sleep quality(From postoperative day 0 to 5)
- Ideal outcome of pancreatoduodenectmoy(postoperative day 30)
- The changes of neuronal damage biomarker level in blood(From the baseline to immediate postoperative state and postoperative day 2)
- The incidence of postoperative delirium(From postoperative day 0 to 5)
- Delirium Rating Scale Revised (DRS-R-98)(From postoperative day 0 to 5)
- non-delirium complications within 30 days after surgery(Within 30 days after surgery)