Effect of Dexmedetomidine on Brain Homeostasis and Neurocognitive Outcome

Effect of Dexmedetomidine on Brain Homeostasis and Neurocognitive Outcome of Patients Undergoing Brain Tumor Exclusion

Brain tumor surgery is commonly associated with different degrees of preoperative intracranial hypertension and surrounding tumor edema, elicited by tumor underlying pathophysiology. During craniotomy for brain tumor resection maintenance of hemodynamic stability and intracranial homoeostasis is of paramount importance. Disordered hemodynamics or adverse stress may activate the immune inflammation or neuroendocrine responses and lead to a surge of inflammatory mediators and stress hormones, which are implicated in secondary brain insults.

Adverse physiological responses caused by intraoperative disordered hemodynamics or surgery-related damage, may lead to some secondary brain injury (such as cerebral edema or cerebral hemorrhage), aggravating damage to brain tissue and affecting the recovery from anesthesia, cognition and prognosis in patients.

Prevention of secondary brain injury is a key-endpoint to improve clinical outcomes in glioma patients undergoing craniotomy.

Alpha2-adrenoceptor agonists have been widely used for sedation, analgesia and anti-sympathetic actions for many years, but the definite evidence of their potential use as neuroprotectants has so far been confined to animal studies, yet the findings are inconsistent.

Dexmedetomidine (DEX) has been demonstrated to be a new type a2 adrenergic receptor (a2-AR) agonist, which can selectively bind with the a1 and a2 adrenergic receptor, and playing a dual role by restraining the activity of sympathetic nervous and stimulating the vagus nerve. Dexmedetomidine (DEX) also plays an important role in in inhibiting inflammatory and neuroendocrine responses. Animal experiments showed that the right must have a dexmedetomidine neuro-protective effect. However, the brain-protective effect of dexmedetomidine in anesthesia of craniotomy resection of glioma has not been reported.

Thus, the aim of this study was to explore the effect of dexmedetomidine on perioperative brain protection, as well as cerebral oxygenation and metabolic status aiming to provide a basis for clinical rational drug use in patients undergoing craniotomy resection of glioma.

Study Overview

• Status: Completed
• Conditions: Inflammatory Response; Brain Tumor; Oxygen Deficiency; Metabolic Disturbance
• Intervention / Treatment: Drug: Dexmedetomidine; Other: Normal saline

Detailed Description

Each participant will receive standard monitoring (ECG, SpO2, SBP, BIS, urine output, temperature). More detailed hemodynamic monitoring will be obtained by Edwards Lifesciences ClearSight system (CO, CI, SV, SVI, SVV, SVR, SVRI).

TCI Propofol and Remifentanil will be the agents of choice for induction and maintenance in anesthesia and cisatracurium will be used for neuromuscular blockade for intubation.

Protective mechanical ventilation will be chosen (7ml/kg IBW) with a respiratory rate to obtain a PaCO2 of 35-40 mmHg. PEEP will be changed for the best PaO2/FiO2 ratio and FiO2 of choice will be 0.5.

The radial artery catheterization will be applied for direct blood pressure measurement and arterial blood gas sampling (pH, PaO2, PaCO2, HCO3, BE, osmolality, lactic acid, Hb, glucose, Na and K will be measured).

The jugular bulb ipsilateral to the craniotomy site will be catheterized for receiving blood samples for blood gas analysis. The following oxygenation and metabolic parameters / derivates will be measured or calculated: SjvO2, pH, PjvO2, PjvCO2, HCO3, BE, Osmolality, Lactic acid jv, Hb, Glucose, Na, K, AjvDO2, AjvCO2, O2ERbr, eRQbr, AjvDL, and LOI.

Dexmedetomidine or normal saline (placebo) administration will start 10 minutes after anesthesia induction and maintained throughout the surgical procedure.

Phases

• T0: 5 minutes before administration of either DEX or placebo
• T15: 10 minutes after administration of either DEX or placebo
• T30: 30 minutes after administration of either DEX or placebo
• T60: 60 minutes after administration of either DEX or placebo
• T120: 120 minutes after administration of either DEX or placebo
• T240: 240 minutes after administration of either DEX or placebo
• End of surgical procedure Blood samples for measuring S-100b, NSE, cortisol, TNF-a and IL-6 will be obtained at phases T0, end of surgery and 24 hours after administration of either DEX or placebo.

Neurocognitive testing will be performed before surgery, 1 week and 1 month later using Karnofsky Performance Status (KFS), Mini Mental State Exam (MMSE), Μontreal Cognitive Assessment (MoCA) and Addenbrooke's Cognitive Exam (ACE III).

Intraoperative consumption of propofol and remifentanil will also be recorded

• Study Type: Interventional
• Enrollment (Actual): 54
• Phase: Phase 4

Contacts and Locations

Study Locations

• Greece
  • Thessaloniki, Greece, 54636
    • Ahepa University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• ASA-PS 1-3 (American Society of Anesthesiologists Physical Status classification)
• Scheduled for elective or semi-elective craniotomy for brain tumor resection
• Signed informed consent

Exclusion Criteria:

• History of craniotomy at the same site
• Morbid obesity
• Delirious person before surgery
• Preoperative heart rate (HR) <45 beats/min or second or third degree AV block
• Treatment with a-methyldopa, clonidine or other a2-adrenergic agonist
• Pregnancy
• Liver or renal failure

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Dexmedetomidine; Dexmedetomidine 2 μg/ml will be given as bolus 1mg/kg for 10 minutes with a maintenance dose of 0.8μg/kg/h until surgery completion	Drug: Dexmedetomidine; Dexmedetomidine 2 μg/ml will be given as bolus 1mg/kg for 10 minutes with a maintenance dose of 0.8μg/kg/h until surgery completion; Other Names: Dexdor
PLACEBO_COMPARATOR: Normal saline; Normal saline (NaCl 0.9%) administration will start 10 minutes after anesthesia induction and maintained throughout the surgical procedure.	Other: Normal saline; Equivalent doses for a solution containing 2mcg/ml of the tested drug calculating for a bolus 1mg/kg for 10 minutes with a maintenance dose of 0.8μg/kg/h until surgery completion; Other Names: NaCl 0.9%

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in S-100b protein	Alterations in S-100b (μg/L) after intravenous infusion of equivalent doses of dexmedetomidine or placebo (normal saline)	End of surgical procedure and 24 hours postoperatively
Changes in NSE	Alterations in NSE (ng/ml) after intravenous infusion of equivalent doses of dexmedetomidine or placebo (normal saline)	End of surgical procedure and 24 hours postoperatively

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in serum cortisol	Alterations in serum cortisol (μg/dl) levels after intravenous infusion of equivalent doses of dexmedetomidine or placebo (normal saline)	End of surgical procedure and 24 hours postoperatively
Changes in serum TNF-a	Alterations in serum TNF-a (pg/ml) levels after intravenous infusion of equivalent doses of dexmedetomidine or placebo (normal saline)	End of surgical procedure and 24 hours postoperatively
Changes in serum IL-6	Alterations in serum IL-6 (pg/ml) levels after intravenous infusion of equivalent doses of dexmedetomidine or placebo (normal saline)	End of surgical procedure and 24 hours postoperatively
Changes in Mini-Mental State Exam (MMSE)	Alterations in Mini-Mental State Exam (MMSE) after intravenous infusion of equivalent doses of dexmedetomidine or placebo (normal saline)	1 week and 1 month after the end of surgical procedure
Changes in Μontreal Cognitive Assessment (MoCA)	Alterations in Μontreal Cognitive Assessment (MoCA) after intravenous infusion of equivalent doses of dexmedetomidine or placebo (normal saline)	1 week and 1 month after the end of surgical procedure
Changes in Addenbrooke's Cognitive Exam (ACE III)	Alterations in Addenbrooke's Cognitive Exam (ACE III) after intravenous infusion of equivalent doses of dexmedetomidine or placebo (normal saline)	1 week and 1 month after the end of surgical procedure

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in jugular venous oxygen saturation	Alterations in jugular venous oxygen saturation (%), after intravenous infusion of equivalent doses of dexmedetomidine or placebo (normal saline)	10, 30, 60, 120, 240 minutes after commencing the infusion of the tested agent and end of surgical procedure
Changes in arterio-jugular oxygen difference (AjvDO2)	Alterations in arterio-jugular oxygen difference (AjvDO2 [ml/dl]), after intravenous infusion of equivalent doses of dexmedetomidine or placebo (normal saline)	10, 30, 60, 120, 240 minutes after commencing the infusion of the tested agent and end of surgical procedure
Changes in arterio-jugular carbon dioxide difference (AjvCO2)	Alterations in arterio-jugular carbon dioxide difference (AjvCO2 [mmHg]), after intravenous infusion of equivalent doses of dexmedetomidine or placebo (normal saline)	10, 30, 60, 120, 240 minutes after commencing the infusion of the tested agent and end of surgical procedure
Changes in brain oxygen extraction ratio (O2Erbr)	Alterations in brain oxygen extraction ratio (O2Erbr [%]), after intravenous infusion of equivalent doses of dexmedetomidine or placebo (normal saline)	10, 30, 60, 120, 240 minutes after commencing the infusion of the tested agent and end of surgical procedure

Collaborators and Investigators

• Sponsor: Georgia Tsaousi
• Investigators: Principal Investigator: Georgia Tsaousi, Professor, Aristotle University Of Thessaloniki

Study record dates

Study Major Dates

• Study Start (ACTUAL): March 12, 2020
• Primary Completion (ACTUAL): November 15, 2021
• Study Completion (ACTUAL): December 15, 2021

Study Registration Dates

• First Submitted: February 2, 2020
• First Submitted That Met QC Criteria: February 10, 2020
• First Posted (ACTUAL): February 12, 2020

Study Record Updates

• Last Update Posted (ACTUAL): February 15, 2022
• Last Update Submitted That Met QC Criteria: February 14, 2022
• Last Verified: February 1, 2022

More Information

Terms related to this study

• Keywords: biomarkers; dexmedetomidine; neuroinflammation; brain metabolism; brain oxygenation; neurocognitive outcome
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neoplasms; Neoplasms by Site; Signs and Symptoms, Respiratory; Central Nervous System Neoplasms; Nervous System Neoplasms; Brain Neoplasms; Hypoxia; 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: DexProB

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• 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