Effect of Dexmedetomidine on Brain Homeostasis and Neurocognitive Outcome

• ClinicalTrials.gov Identifier: NCT04266665
• Recruitment Status: Completed
• First Posted: February 12, 2020
• Last Update Posted: February 15, 2022
• Sponsor: Georgia Tsaousi
• Information provided by (Responsible Party): Georgia Tsaousi, Aristotle University Of Thessaloniki

Tracking Information

• First Submitted Date: February 2, 2020
• First Posted Date: February 12, 2020
• Last Update Posted Date: February 15, 2022
• Actual Study Start Date: March 12, 2020
• Actual Primary Completion Date: November 15, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 10, 2020)

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

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: February 10, 2020)

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

• Original Secondary Outcome Measures: Same as current

Current Other Pre-specified Outcome Measures (submitted: February 10, 2020)

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

• Original Other Pre-specified Outcome Measures: Same as current

Descriptive Information

• Brief Title: Effect of Dexmedetomidine on Brain Homeostasis and Neurocognitive Outcome
• Official Title: Effect of Dexmedetomidine on Brain Homeostasis and Neurocognitive Outcome of Patients Undergoing Brain Tumor Exclusion

Brief Summary

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.

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
• Study Phase: Phase 4
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Investigator, Outcomes Assessor); Primary Purpose: Treatment

Condition

• Brain Tumor
• Metabolic Disturbance
• Inflammatory Response
• Oxygen Deficiency

Intervention

• 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 Name: Dexdor
• 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 Name: NaCl 0.9%

Study Arms

• 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
  Intervention: Drug: Dexmedetomidine
• Placebo Comparator: Normal saline
  Normal saline (NaCl 0.9%) administration will start 10 minutes after anesthesia induction and maintained throughout the surgical procedure.
  Intervention: Other: Normal saline

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: February 14, 2022): 54
• Original Estimated Enrollment (submitted: February 10, 2020): 56
• Actual Study Completion Date: December 15, 2021
• Actual Primary Completion Date: November 15, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 80 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Greece

Administrative Information

• NCT Number: NCT04266665
• Other Study ID Numbers: DexProB
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• 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

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Georgia Tsaousi, Aristotle University Of Thessaloniki
• Original Responsible Party: Same as current
• Current Study Sponsor: Georgia Tsaousi
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

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

• PRS Account: Aristotle University Of Thessaloniki
• Verification Date: February 2022