A Lithium-Based Medication to Improve Neurological Outcomes After Surgical Carotid Reconstruction

A Lithium-Based Medication to Improve Neurological Outcomes After Surgical Carotid Reconstruction: A Double-Blind, Placebo Control Randomized Trial (BINOS)

There are 10.3 million cases of stroke registered in the world every year; 63% of them lead to death. According to World Health Organization, stroke is one of the most important risk factors of death and early disability.

Carotid artery surgery is a gold standard of hemodynamically significant carotid artery disease treatment. According to some trials, carotid artery surgery decreases the 2-years mortality.

The most important part of carotid artery surgery is a temporary absence of blood flow in the carotid artery. The duration of this period is a crucial characteristic of this type of surgery. The absence of blood flow leads to brain ischemia which is the risk factor of postoperative neurocognitive disorders such as emergence delirium, postoperative delirium and postoperative cognitive dysfunction.

Some surgical and non-surgical methods for brain protection were evaluated. According to recent data, there is no evidence of effective pharmacological protective methods that can decrease brain damage during carotid artery surgery.

Nevertheless, some trials demonstrated that using lithium-based medications for patients with a stroke can reduce the volume of the stroke. Therefore, the investigators want to check the hypothesis that using lithium-based medication in the preoperative period can reduce brain damage during carotid artery surgery.

The objectives of this trial:

1. To determine if Lithium carbonate is superior to placebo for the occurrence of emergence delirium, agitation, postoperative delirium and postoperative cognitive dysfunction.
2. To determine if Lithium carbonate is non-inferior to placebo for the occurrence of a new arrhythmia, leukocytosis, acute kidney injury, seizure disorders, diarrhea, nausea, and vomit.

Study Overview

• Status: Recruiting
• Conditions: Carotid Artery Diseases; Carotid Artery Stenosis
• Intervention / Treatment: Drug: Lithium Carbonate; Drug: Placebo

Detailed Description

There are 10.3 million cases of stroke registered in the world every year; 63% of them lead to death. According to World Health Organization, stroke is one of the most important risk factors of death and early disability.

Carotid artery surgery is a gold standard of hemodynamically significant carotid artery disease treatment. According to some trials, carotid artery surgery decreases the 2-years mortality.

The most important part of carotid artery surgery is a temporary absence of blood flow in the carotid artery. The duration of this period is a crucial characteristic of this type of surgery. The absence of blood flow leads to brain ischemia which is the risk factor of postoperative neurocognitive disorders such as emergence delirium, postoperative delirium and postoperative cognitive dysfunction.

Some surgical and non-surgical methods for brain protection were evaluated. According to recent data, there is no evidence of effective pharmacological protective methods that can decrease brain damage during carotid artery surgery.

Nevertheless, some trials demonstrated that using lithium-based medications for patients with a stroke can reduce the volume of the stroke. Therefore, the investigators want to check the hypothesis that using lithium-based medication in the preoperative period can reduce brain damage during carotid artery surgery.

The objectives of this trial:

To determine if Lithium carbonate is superior to placebo for the occurrence of emergence delirium, agitation, postoperative delirium and postoperative cognitive dysfunction.

To determine if Lithium carbonate is non-inferior to placebo for the occurrence of a new arrhythmia, leukocytosis, acute kidney injury, seizure disorders, diarrhea, nausea, and vomit.

• Study Type: Interventional
• Enrollment (Estimated): 500
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Valery Likhvantsev, PhD; Phone Number: +79036235982; Email: lik0704@gmail.com
• Study Contact Backup: Name: Levan Berikashvili, MD; Phone Number: +79263308968; Email: levan.berikashvili@mail.ru

Study Locations

• Russian Federation
  • Moscow, Russian Federation
    • Recruiting
    • Demikhov Municipal Clinical Hospital 68
    • Contact: Levan Berikashvili; Phone Number: +79263308968; Email: levan.berikashvili@mail.ru
  • Moscow, Russian Federation, 117997
    • Recruiting
    • Vishnevsky Center of Surgery
    • Contact: George Plotnikov, PhD; Phone Number: +79253117509; Email: georgpp@mail.ru
    • Contact: Roman Kornelyuk, PhD; Phone Number: +79234836510; Email: rkornelyuk@mail.ru
    • Principal Investigator: George Plotnikov, PhD
    • Sub-Investigator: Roman Kornelyuk, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• age > 18 years
• elective carotid artery surgery
• general anesthesia
• written informed consent

Exclusion Criteria:

• urgent surgery
• recent ( < 1 month) overt stroke
• Mini-mental State Examination < 20 points
• The presence of any mental disorder according to the International Classification of Diseases 11th Revision which is confirmed by a psychiatrist.
• The presence of any neuromuscular disease according to the International Classification of Diseases 11th Revision
• Hypersensitivity or known allergy to lithium carbonate
• History of seizure disorder
• History of leukemia
• Estimated glomerular filtration rate < 30 ml/min/1.73 m2
• Left ventricular ejection fraction < 30%
• Heart failure equal 3 or 4 class according to the New York Heart Association Functional Classification
• Pregnant or breast-feeding women
• Inability to undergo a preoperative assessment for any reason
• Previously enrolled in this trial

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Lithium; In preoperative period patients will take 300mg of lithium carbonate on 1-1-1 regimen during 2 days prior to surgery. On the day of surgery, they will take 300mg of lithium carbonate 2 hours before surgery. After the surgery, patients will take 300mg of lithium carbonate in the afternoon and 300mg of lithium carbonate in the evening.	Drug: Lithium Carbonate; In preoperative period patients will take 300 mg of lithium carbonate on 1-1-1 regimen during 2 days prior to surgery. On the day of surgery they will take 300mg of lithium carbonate 2 hours before surgery.
Placebo Comparator: Placebo; In preoperative period patients will take placebo on 1-1-1 regimen during 2 days prior to surgery. On the day of surgery, they will take placebo 2 hours before surgery. After the surgery, patients will take placebo in the afternoon and in the evening.	Drug: Placebo; In preoperative period patients will take placebo on 1-1-1 regimen during 2 days prior to surgery. On the day of surgery they will placebo 2 hours before surgery.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Frequency of emergence delirium	Number of patients with positive the confusion assessment method for the intensive care unit as soon as they reach Aldrete score of 9 points	30 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Frequency of agitation	Richmond agitation-sedation scale more or equal +2 evaluated from the end of volatile anesthetic supply to the moment when a patient reaches Aldrete score of 9 points Richmond agitation-sedation scale: minimum value = -5 (Unarousable - no response to voice or physical stimulation) maximum value = +4 (Combative - overtly combative or violent; immediate danger to staff) Adequate patients have the results of Richmond agitation-sedation score equal 0 (Alert and calm; Spontaneously pays attention to caregiver)	30 days
Frequency of postoperative delirium	Number of patients with even one positive confusion assessment method for the intensive care unit or 3-minute confusion assessment method	30 days
Length of postoperative delirium	30 days - number of days in which patient had positive confusion assessment method for the intensive care unit or 3-minute confusion assessment method	until 1 month after surgery
Frequency of overt strokes	Number of overt strokes	1 year
Frequency of covert strokes	Number of covert strokes	1 year
Length of stay in intensive care unit	Number of days in intensive care unit	1 month
Length of hospitalization	Number of days in hospital	1 month
Frequency of cardiac death	Number of of cardiac deaths	1 year
Frequency of non-fatal cardiac arrest	Number of non-fatal cardiac arrests	1 year
Frequency of major adverse cardiac event	Number of major adverse cardiac events	1 year
Frequency of major adverse cardiac and cognitive event	Number of major adverse cardiac and cognitive events	1 year
30-days mortality	Number of deaths in period of 30 days after surgery	30 days
1-year mortality	Number of deaths in period of 1 year after surgery	1 year
Frequency of new postoperative arrhythmia	Number of new postoperative arrhythmias	1 month
Frequency of leukocytosis	Number of patients with leukocytosis	From 2 days before surgery to the day of surgery
Frequency of acute diarrhea	Number of patients with acute diarrhea	From 2 days before surgery to the day of surgery
Frequency of postoperative nausea and vomit	Number of patients with postoperative nausea and vomit	1 month
Frequency of preoperative nausea and vomit	Number of patients with preoperative nausea and vomit	From 2 days before surgery to the day of surgery
Frequency of acute kidney injury	Number of patients with acute kidney injury	1 month
Frequency of myasthenia	Number of patients with myasthenia	From 2 days before surgery to the day of surgery
Frequency of preoperative seizure	Number of patients with seizure	From 2 days before surgery to the day of surgery
Frequency of postoperative seizure	Number of patients with seizure	1 month
Serum level of S100 beta protein	Serum level of S100 beta protein	2 days after surgery
Serum level of neuron-specific enolase	Serum level of neuron-specific enolase	2 days after surgery
Serum level of Tau-protein	Serum level of Tau-protein	2 days after surgery
Serum level of Neurofilament light polypeptide	Serum level of Neurofilament light polypeptide	2 days after surgery
Serum level of Glial fibrillary acidic protein	Serum level of Glial fibrillary acidic protein	2 days after surgery

Collaborators and Investigators

• Sponsor: Negovsky Reanimatology Research Institute
• Collaborators: Demikhov Municipal Clinical Hospital 68
• Investigators: Principal Investigator: Valery Likhvantsev, PhD, Negovsky Reanimatology Research Institute

Study record dates

Study Major Dates

• Study Start (Actual): November 20, 2021
• Primary Completion (Estimated): December 20, 2025
• Study Completion (Estimated): November 20, 2026

Study Registration Dates

• First Submitted: October 1, 2021
• First Submitted That Met QC Criteria: November 8, 2021
• First Posted (Actual): November 18, 2021

Study Record Updates

• Last Update Posted (Actual): January 25, 2024
• Last Update Submitted That Met QC Criteria: January 24, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Stroke; Neuroinflammation; Emergence delirium; Agitation; Postoperative delirium; Lithium; Carotid artery stenosis; Neurocognitive disorders; Carotid artery diseases; Carotid artery surgery; Postoperative cognitive disorders
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Arterial Occlusive Diseases; Carotid Stenosis; Carotid Artery Diseases; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Enzyme Inhibitors; Tranquilizing Agents; Psychotropic Drugs; Antidepressive Agents; Antimanic Agents; Lithium Carbonate
• Other Study ID Numbers: BINOS

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No