Modulating Surgery-Induced Blood-Brain Barrier Disruption in Elderly

Modulating Surgery-Induced Blood-Brain Barrier Disruption in Elderly: Impact of Dexmedetomidine and Lidocaine, a Randomized Controlled Trial

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.

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.

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.

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.

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.

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.

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

Intensive Care Unit (CAM-ICU) and 3-min diagnostic interview for CAM (3D-CAM) for ICU patients and ward patients, respectively

The degree of surgical pain will be assessed at rest, when taking a deep breath, and when moving by NRS.

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

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

Study data may be made available on request to the principal investigators with an appropriate research and data-protection plan agreed on.