Modulating Surgery-Induced Blood-Brain Barrier Disruption in Elderly

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.

Eligibility Criteria:
Inclusion Criteria:

1. American Society of Anesthesiologists (ASA) physical status classification I-III
2. Undergoing elective open pancreatoduodenectomy
3. Voluntary participation in the trial and signed informed consent

Exclusion Criteria:

1. 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.
2. Concurrent treatment with a class 1 antiarrhythmic or amiodarone)
3. History of hypersensitivity reactions or contraindications to the study drugs (dexmedetomidine or lidocaine).
4. Patient at personal of familial risk of malignant hyperthermia and porphyria
5. Body mass index (BMI) ˃40 kg/m2
6. 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.
7. History of severe hepatic (Childs-Pugh Score \> Class A ) or renal (glomerular filtration rate \<30m)/min×1.73m2) disorders.
8. Severe audio-visual impairments, or inability to speak precluding communication.
9. Evidence of preoperative delirium (Confusion Assessment Method, CAM)
10. History of uncontrolled seizures.
11. Patients on immunosuppressants (e.g., steroids) or immunomodulatory therapy, chemotherapeutic agents with known cognitive effects.
12. Patients taking the following drugs that are moderate-strong inhibitors of the CYP1A2 and CYP3A4 metabolic pathways within 72 hours prior to surgery